NM_000492.3(CFTR):c.1521_1523del (p.Phe508del) AND Cystic fibrosis

Clinical significance:Pathogenic (Last evaluated: Mar 3, 2004)

Review status:4 stars out of maximum of 4 stars

practice guideline

Based on:
24 submissions [Details]
Record status:
current
Accession:
RCV000007523.35

Allele description [Variation Report for NM_000492.3(CFTR):c.1521_1523del (p.Phe508del)]

NM_000492.3(CFTR):c.1521_1523del (p.Phe508del)

Genes:
CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]
CFTR-AS1:CFTR antisense RNA 1 [Gene - HGNC]
Variant type:
Deletion
Cytogenetic location:
7q31.2
Genomic location:
Preferred name:
NM_000492.3(CFTR):c.1521_1523del (p.Phe508del)
Other names:
F508del; deltaF508; F508delF; DF508; Phe508del; DeltaF508
HGVS:
  • NC_000007.13:g.117199645_117199647del
  • NC_000007.14:g.117559592_117559594del
  • NG_016465.4:g.98809_98811del
  • NM_000492.3:c.1521_1523del
  • NM_000492.4:c.1521_1523delMANE SELECT
  • NP_000483.3:p.Phe508del
  • NP_000483.3:p.Phe508del
  • NP_000483.3:p.Phe508del
  • NP_000483.3:p.Phe508del
  • NP_000483.3:p.Phe508del
  • LRG_663t1:c.1521_1523del
  • LRG_663:g.98809_98811del
  • LRG_663p1:p.Phe508del
  • NC_000007.13:g.117199645_117199647del
  • NC_000007.13:g.117199646_117199648del
  • NC_000007.13:g.117199646_117199648delCTT
  • NG_016465.1:g.84630_84632delCTT
  • NM_000492.3:c.1520_1522del
  • NM_000492.3:c.1520_1522delTCT
  • NM_000492.3:c.1521_1523delCTT
  • NM_000492.4:c.1521_1523delCTTMANE SELECT
Protein change:
PHE508DEL
Links:
PharmGKB: 1447979749; PharmGKB: 981755820; PharmGKB: 981755820PA165950341; PharmGKB Clinical Annotation: 981755820; OMIM: 602421.0001; dbSNP: rs113993960
NCBI 1000 Genomes Browser:
rs113993960
Molecular consequence:
  • NM_000492.3:c.1521_1523del - inframe_deletion - [Sequence Ontology: SO:0001822]
  • NM_000492.4:c.1521_1523del - inframe_deletion - [Sequence Ontology: SO:0001822]
Functional consequence:
loss_of_function_variant [Sequence Ontology: SO:0002054]
Observations:
17

Condition(s)

Name:
Cystic fibrosis (CF)
Synonyms:
Mucoviscidosis
Identifiers:
MONDO: MONDO:0009061; MedGen: C0010674; Orphanet: 586; OMIM: 219700

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000027724OMIMno assertion criteria providedPathogenic
(May 17, 2015)
germlineliterature only

PubMed (23)
[See all records that cite these PMIDs]

Grebe, T. A., Seltzer, W. K., DeMarchi, J., Silva, D. K., Doane, W. W., Gozal, D., Richter, S. F., Bowman, C. M., Norman, R. A., Rhodes, S. N., Hernried, L. S., Murphy, S., Harwood, I. R., Accurso, F. J., Jain, K. D. Genetic analysis of Hispanic individuals with cystic fibrosis. Am. J. Hum. Genet. 54: 443-446, 1994.,

SCV000071392American College of Medical Genetics and Genomics (ACMG) - The ACMG recommended carrier screening panelpractice guideline
pathogenic
(Mar 3, 2004)
germlinecuration

PubMed (1)
[See all records that cite this PMID]

SCV000071493CFTR2 - CFTR2reviewed by expert panel
Pathogenic
(Mar 17, 2017)
germlineresearch

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV000074347Invitaecriteria provided, single submitter
Pathogenic
(Oct 29, 2020)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV000221179Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Pathogenic
(Apr 2, 2020)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV000536740Division of Human Genetics,Children's Hospital of Philadelphia - CSER-PediSeqno assertion criteria providedPathogenic
(Jun 10, 2016)
maternalresearch

PubMed (7)
[See all records that cite these PMIDs]

SCV000538017Knight Diagnostic Laboratories, Oregon Health and Sciences University - CSER-NextGencriteria provided, single submitter
Pathogenic
(Mar 30, 2016)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000584079HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-HudsonAlphacriteria provided, single submitter
Pathogenic
(Oct 21, 2013)
paternal, maternal, unknownresearch

HA_assertions_20150911.pdf,

Citation Link,

SCV000594089Genetic Services Laboratory,University of Chicagocriteria provided, single submitter
Pathogenic
(Aug 26, 2016)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000607274GenomeConnect, ClinGenno assertion providednot providedunknownphenotyping only

SCV000864219Johns Hopkins Genomics, Johns Hopkins Universitycriteria provided, single submitter
Pathogenic
(Jan 15, 2019)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000883108Equipe Genetique des Anomalies du Developpement, Université de Bourgognecriteria provided, single submitter
Pathogenic
(Jun 4, 2019)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000886152Mendelicscriteria provided, single submitter
Pathogenic
(Nov 5, 2018)
unknownclinical testing

Citation Link,

SCV000891676Department of Genetics,Sultan Qaboos University Hospital, Omancriteria provided, single submitter
Pathogenic
(Dec 30, 2017)
unknownclinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV001149705Institute of Human Genetics, Klinikum rechts der Isarcriteria provided, single submitter
Pathogenic
(Jan 17, 2020)
inheritedclinical testing

Citation Link,

SCV001161676Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Geneticscriteria provided, single submitter
Pathogenic
(Oct 18, 2019)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001169465CFTR-Francecriteria provided, single submitter
Pathogenic
(Jan 29, 2018)
germlinecuration

PubMed (1)
[See all records that cite this PMID]

SCV001193905Myriad Women's Health, Inc.criteria provided, single submitter
Pathogenic
(Oct 18, 2019)
unknownclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV001244997Victorian Clinical Genetics Services,Murdoch Childrens Research Institutecriteria provided, single submitter
Pathogenic
(Sep 3, 2018)
maternalclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001251533UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill - NSIGHT-NC NEXUScriteria provided, single submitter
Pathogenicgermlineresearch

PubMed (2)
[See all records that cite these PMIDs]

SCV001424387Centogene AG - the Rare Disease Companycriteria provided, single submitter
Pathogenicgermlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001527339Baylor Geneticscriteria provided, single submitter
Pathogenic
(Aug 30, 2018)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001622798GeneReviewsno assertion criteria providedPathogenic
(Feb 2, 2017)
unknownliterature only

PubMed (2)
[See all records that cite these PMIDs]

SCV001810348Nilou-Genome Labcriteria provided, single submitter
Pathogenic
(Jul 22, 2021)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Description

carrier finding

SCV001251533

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineno2not providednot providednot providednot providedclinical testing, research
not providedinheritedyes1not providednot provided1not providedclinical testing
not providedmaternalunknown91not provided7not providedresearch, clinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing, research, curation
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknown24not providednot provided24not providedliterature only, clinical testing, research, phenotyping only
not providedgermlineunknown1916not providednot providednot providedclinical testing, curation
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedpaternalunknown4not providednot provided4not providedresearch
Indian Hindugermlineyes1not providednot providednot providednot providedclinical testing

Citations

PubMed

Liquid movement across the surface epithelium of large airways.

Chambers LA, Rollins BM, Tarran R.

Respir Physiol Neurobiol. 2007 Dec 15;159(3):256-70. Epub 2007 Jun 17. Review.

PubMed [citation]
PMID:
17692578
PMCID:
PMC2696130

Heterogeneous spectrum of mutations in CFTR gene from Indian patients with congenital absence of the vas deferens and their association with cystic fibrosis genetic modifiers.

Sharma H, Mavuduru RS, Singh SK, Prasad R.

Mol Hum Reprod. 2014 Sep;20(9):827-35. doi: 10.1093/molehr/gau047. Epub 2014 Jun 23.

PubMed [citation]
PMID:
24958810
See all PubMed Citations (42)
PMC

Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel.

Watson MS, Cutting GR, Desnick RJ, Driscoll DA, Klinger K, Mennuti M, Palomaki GE, Popovich BW, Pratt VM, Rohlfs EM, Strom CM, Richards CS, Witt DR, Grody WW.

Genetics in Medicine. 2004 Sep-Oct; 6(5): 387-391

PMC [article]
PMCID:
PMC3110945
PMID:
15371902
DOI:
10.1097/01.GIM.0000139506.11694.7C

Details of each submission

From OMIM, SCV000027724.9

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (23)

Description

In individuals with cystic fibrosis (CF; 219700), Kerem et al. (1989) identified deletion of 3 basepairs in exon 10 of the CFTR gene, leading to deletion of phenylalanine at codon 508 (delta-F508). The exon in which the delta-F508 mutation occurs has been corrected to exon 11; see, e.g., Sharma et al. (2014).

The European Working Group on CF Genetics (1990) published information on the distribution of the delta-F508 mutation in Europe. The data, illustrated with a useful map, indicated a striking cline across Europe from low values of 30% in the southeast (in Turkey) to high values in the northwest (e.g., 88% in Denmark). The group suggested that the spread of the CF gene might have accompanied the migrations of early farmers starting from the Middle East and slowly progressing toward the northwest of Europe. The diffusion of the gene may have been favored by the selective advantage conferred by the gene. Strong association with the so-called haplotype B was demonstrated. The possibility of 'hitchhiking,' i.e., the influence of neighboring genes was discussed. Rozen et al. (1990) found the delta-F508 mutation in 71% of CF chromosomes from urban Quebec province French Canadian families, 55% of those from Saguenay-Lac-Saint-Jean region families and in 70% of those from Louisiana Acadian families. De Braekeleer (1991) estimated that the frequency at birth of cystic fibrosis is 1/926 in the Saguenay-Lac-Saint-Jean region, giving a carrier rate of 1/15. For the same region, Daigneault et al. (1991) reported a prevalence of CF at birth of 1/902 liveborns, and a carrier rate of 1/15. Rozen et al. (1992) found that the delta-F508 mutation was present in 58% of Saguenay-Lac-Saint-Jean CF families, with the G-to-T donor splice site mutation after codon 621 being found in 23%, and the A455E mutation (602421.0007) in 8%. The latter 2 mutations were not found in urban Quebec families. This provided further evidence of the role of founder effect. Among 293 patients, Kerem et al. (1990) found that those who were homozygous for the F508 deletion had received a diagnosis of cystic fibrosis at an earlier age and had a greater frequency of pancreatic insufficiency. Pancreatic insufficiency was present in 99% of the homozygous patients, 72% of those heterozygous for the deletion, and only 36% of patients with other mutations. Wauters et al. (1991) studied the frequency of the delta-F508 mutation among Belgian patients with CF. The mutation was present in 80% of CF chromosomes from 36 unrelated families. Ninety-three percent of the CF chromosomes carrying the delta-F508 mutation also carried haplotype B in this population. Gille et al. (1991) described a strategy for efficient heterozygote screening for the delta-F508 mutation. They showed that PCR could detect a heterozygote in a pool of up to 49 unrelated DNA samples. Lerer et al. (1992) reported that the delta-F508 mutation accounts for 33.8% of Jewish CF alleles.

The Basque population is thought to be one of the oldest in Europe, having been established in western Europe during the late Paleolithic Age. Euskera, the Basque language, is thought to be pre-Indo-European, originating from the first settlers of Europe. The variable distribution of the delF508 mutation in Europe, with higher frequencies in northern Europe and lower frequencies in southern Europe, has been attributed to a spread of the mutation by early farmers migrating from the Middle East during the Neolithic period. However, a very high frequency of this mutation was found in the Basque Provinces, where the incidence of CF is approximately 1 in 4,500. In a study of 45 CF families from the Basque Provinces, Casals et al. (1992) found that the frequency of the delF508 mutation was 87% in the chromosomes of individuals of pure Basque extraction and 58% in those of mixed Basque origin. Casals et al. (1992) proposed that the delF508 mutation was present in Europe more than 10,000 years ago, preceding the agricultural migrations which diluted the mutation rather than introducing it. Ballabio et al. (1990) described an allele-specific amplification method for diagnosing the phenylalanine-508 deletion. Among Pueblo and Navajo Native Americans of the U.S. Southwest, Grebe et al. (1992) found no instance of the delF508 mutation in 12 affected individuals. Clinically, 6 of the affected individuals had growth deficiency and 5 (all from the Zuni Pueblo) had a severe CF phenotype. Four of the 6 Zunis with CF were also microcephalic, a finding not previously noted in CF patients. In an analysis of 640 Spanish cystic fibrosis families, Casals et al. (1997) found that 75 mutations accounted for 90.2% of CF chromosomes - an extraordinarily high heterozygosity. The frequency of the delta-F508 mutation was 53.2%. The next most frequent mutation was gly542 to ter (602421.0009) with a frequency of 8.43%.

Using 3 intragenic microsatellites of the CFTR gene located in introns, Russo et al. (1995) evaluated linkage disequilibrium between each marker and various CF mutations on a total of 377 CF and 358 normal chromosomes from Italian subjects. Results were considered consistent with the hypothesis that all del508 chromosomes derived from a single mutational event. The same hypothesis was valid for 3 other mutations which might have originated more recently than del508.

Grebe et al. (1994) performed molecular genetic analyses on 129 Hispanic individuals with cystic fibrosis in the southwestern United States. Only 46% (59 of 129) carried mutation F508del (frequency in the general population 67.1%).

In 69 Italian patients with CF due to homozygosity for the delF508 mutation, De Rose et al. (2005) found that those who also carried the R131 allele of the immunoglobulin Fc-gamma receptor II gene (FCGR2A; see 146790.0001) had a 4-fold increased risk of acquiring chronic Pseudomonas aeruginosa infection (p = 0.042). De Rose et al. (2005) suggested that FCGR2A locus variability contributes to this infection susceptibility in CF patients.

In a 62-year-old woman with idiopathic bronchiectasis (BESC1; 211400) and elevated sweat chloride but normal nasal potential difference, who carried a heterozygous F508del CFTR mutation, Fajac et al. (2008) also identified heterozygosity for a missense mutation in the SCNN1B gene (600760.0015). The patient had a forced expiratory volume in 1 second (FEV1) that was 89% of predicted. Fajac et al. (2008) concluded that variants in SCNN1B may be deleterious for sodium channel function and lead to bronchiectasis, especially in patients who also carry a mutation in the CFTR gene.

Okiyoneda et al. (2010) identified the components of the peripheral protein quality control network that removes unfolded CFTR containing the F508del mutation from the plasma membrane. Based on their results and proteostatic mechanisms at different subcellular locations, Okiyoneda et al. (2010) proposed a model in which the recognition of unfolded cytoplasmic regions of CFTR is mediated by HSC70 (600816) in concert with DNAJA1 (602837) and possibly by the HSP90 machinery (140571). Prolonged interaction with the chaperone-cochaperone complex recruits CHIP (607207)-UBCH5C (602963) and leads to ubiquitination of conformationally damaged CFTR. This ubiquitination is probably influenced by other E3 ligases and deubiquitinating enzyme activities, culminating in accelerated endocytosis and lysosomal delivery mediated by Ub-binding clathrin adaptors and the endosomal sorting complex required for transport (ESCRT) machinery, respectively. In an accompanying perspective, Hutt and Balch (2010) commented that the 'yin-yang' balance maintained by the proteostasis network is critical for normal cellular, tissue, and organismal physiology.

Among 1,482 Schmiedeleut (S-leut) Hutterites from the United States, Chong et al. (2012) found 32 heterozygotes and no homozygotes for the phe508del mutation in the CFTR gene, for a frequency of 0.022, or 1 in 45.5. This frequency is lower than that for the general population for this mutation, which is 1 in 30.

Pankow et al. (2015) reported the first comprehensive analysis of the CFTR and delta-F508 CFTR interactome and its dynamics during temperature shift and inhibition of histone deacetylases. By using a novel deep proteomic analysis method, they identified 638 individual high-confidence CFTR interactors and discovered a delta-F508 deletion-specific interactome, which is extensively remodeled upon rescue. Detailed analysis of the interactome remodeling identified key novel interactors, whose loss promote delta-F508i CFTR channel function in primary cystic fibrosis epithelia or which are critical for CFTR biogenesis. The results of Pankow et al. (2015) demonstrated that global remodeling of delta-F508 CFTR interactions is crucial for rescue, and provided comprehensive insight into the molecular disease mechanisms of cystic fibrosis caused by deletion of F508.

Clinical Trials

Wainwright et al. (2015) conducted two phase 3, randomized, double-blind, placebo-controlled studies that were designed to assess the effects of lumacaftor (VX-809), a CFTR corrector, in combination with ivacaftor (VX-770), a CFTR potentiator. A total of 1,108 patients 12 years of age or older who were homozygous for the Phe508del CFTR mutation were randomly assigned to receive either lumacaftor (600 mg once daily or 400 mg every 12 hours) in combination with ivacaftor (250 mg every 12 hours) or matched placebo for 24 weeks. The primary endpoint was the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1) at week 24. In both studies, there were significant improvements in the primary endpoint. The difference between active and placebo with respect to mean absolute improvement in the percentage FEV1 ranged from 2.6 to 4.0 percentage points (p less than 0.001), which corresponded to a mean relative treatment difference of 4.3 to 6.7% (p less than 0.001). Pooled analyses showed that the rate of pulmonary exacerbations was 30 to 39% lower in the treated groups than in the placebo group. In addition, the rate of events leading to hospitalization or the use of intravenous antibiotics was lower in the treated groups. The incidence of adverse events was similar in the treated and placebo groups. The rate of discontinuation due to an adverse event was 4.2% among patients who received lumacaftor-ivacaftor versus 1.6% among those who received placebo. Wainwright et al. (2015) concluded that the combination of a CFTR corrector and potentiator, designed to address the underlying cause of cystic fibrosis by targeting CFTR, can benefit the 45% of patients who are homozygous for the Phe508del mutation.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From American College of Medical Genetics and Genomics (ACMG) - The ACMG recommended carrier screening panel, SCV000071392.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (1)

Description

Converted during submission to Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From CFTR2 - CFTR2, SCV000071493.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000074347.11

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change deletes 3 nucleotides from exon 11 of the CFTR mRNA (c.1521_1523delCTT). This leads to the deletion of one amino acid residue in the CFTR protein (p.Phe508del) but otherwise preserves the integrity of the reading frame. This single amino acid deletion (also known as ∆F508) disrupts protein function and is the most common cause of cystic fibrosis (PMID: 2475911, 15371902, 23974870). For these reasons, it has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000221179.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided19not providednot providedclinical testing PubMed (6)

Description

proposed classification - variant undergoing re-assessment, contact laboratory

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided19not provided16not provided

From Division of Human Genetics,Children's Hospital of Philadelphia - CSER-PediSeq, SCV000536740.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (7)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1maternalunknownnot providednot providednot providednot providednot providednot providednot provided

From Knight Diagnostic Laboratories, Oregon Health and Sciences University - CSER-NextGen, SCV000538017.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

The c.1521_1523delCTT (p.Phe508del), also known as ΔF508, is an in-frame deletion in the CFTR gene. This variant is the most common CF-causing mutation, accounting for an estimated 72% of mutant alleles in people of European ancestry (Watson et al., 2004). This p.Phe508del variant is classified as a class II mutation that blocks the processing of the CFTR protein (Welsh et al., 2001). This variant has been reported at low frequencies (1.0%) in 1000 Genomes and ExAc population databases, but has not been reported in the Exome Sequencing Project database (ESP). The CFTR2 database has 32,833 patients that have this mutation, which they classify as CF-causing (http://www.cftr2.org/mutation.php?view=general&mutation_id=1). Therefore, this collective evidence supports the classification of the c.1521_1523delCTT (p.Phe508del) as a recessive pathogenic variant for Cystic fibrosis.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenonot providednot providednot providednot providednot providednot providednot provided

From HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-HudsonAlpha, SCV000584079.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedresearchnot provided
2not provided1not providednot providedresearchnot provided
3not provided1not providednot providedresearchnot provided
4not provided1not providednot providedresearchnot provided
5not provided1not providednot providedresearchnot provided
6not provided1not providednot providedresearchnot provided
7not provided1not providednot providedresearchnot provided
8not provided1not providednot providedresearchnot provided
9not provided1not providednot providedresearchnot provided
10not provided1not providednot providedresearchnot provided
11not provided1not providednot providedresearchnot provided
12not provided1not providednot providedresearchnot provided
13not provided1not providednot providedresearchnot provided
14not provided1not providednot providedresearchnot provided
15not provided1not providednot providedresearchnot provided
16not provided1not providednot providedresearchnot provided
17not provided1not providednot providedresearchnot provided
18not provided1not providednot providedresearchnot provided
19not provided1not providednot providedresearchnot provided
20not provided1not providednot providedresearchnot provided
21not provided1not providednot providedresearchnot provided
22not provided1not providednot providedresearchnot provided
23not provided1not providednot providedresearchnot provided
24not provided1not providednot providedresearchnot provided
25not provided1not providednot providedresearchnot provided
26not provided1not providednot providedresearchnot provided
27not provided1not providednot providedresearchnot provided
28not provided1not providednot providedresearchnot provided
29not provided1not providednot providedresearchnot provided
30not provided1not providednot providedresearchnot provided
31not provided1not providednot providedresearchnot provided
32not provided1not providednot providedresearchnot provided
33not provided1not providednot providedresearchnot provided
34not provided1not providednot providedresearchnot provided
35not provided1not providednot providedresearchnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknown1not providednot provided1not providednot providednot provided
2paternalunknown1not providednot provided1not providednot providednot provided
3unknownunknown1not providednot provided1not providednot providednot provided
4unknownunknown1not providednot provided1not providednot providednot provided
5unknownunknown1not providednot provided1not providednot providednot provided
6unknownunknown1not providednot provided1not providednot providednot provided
7unknownunknown1not providednot provided1not providednot providednot provided
8unknownunknown1not providednot provided1not providednot providednot provided
9paternalunknown1not providednot provided1not providednot providednot provided
10unknownunknown1not providednot provided1not providednot providednot provided
11paternalunknown1not providednot provided1not providednot providednot provided
12unknownunknown1not providednot provided1not providednot providednot provided
13maternalunknown1not providednot provided1not providednot providednot provided
14unknownunknown1not providednot provided1not providednot providednot provided
15unknownunknown1not providednot provided1not providednot providednot provided
16paternalunknown1not providednot provided1not providednot providednot provided
17unknownunknown1not providednot provided1not providednot providednot provided
18maternalunknown1not providednot provided1not providednot providednot provided
19unknownunknown1not providednot provided1not providednot providednot provided
20maternalunknown1not providednot provided1not providednot providednot provided
21unknownunknown1not providednot provided1not providednot providednot provided
22unknownunknown1not providednot provided1not providednot providednot provided
23maternalunknown1not providednot provided1not providednot providednot provided
24unknownunknown1not providednot provided1not providednot providednot provided
25maternalunknown1not providednot provided1not providednot providednot provided
26unknownunknown1not providednot provided1not providednot providednot provided
27maternalunknown1not providednot provided1not providednot providednot provided
28unknownunknown1not providednot provided1not providednot providednot provided
29maternalunknown1not providednot provided1not providednot providednot provided
30unknownunknown1not providednot provided1not providednot providednot provided
31unknownunknown1not providednot provided1not providednot providednot provided
32unknownunknown1not providednot provided1not providednot providednot provided
33unknownunknown1not providednot provided1not providednot providednot provided
34unknownunknown1not providednot provided1not providednot providednot provided
35unknownunknown1not providednot provided1not providednot providednot provided

From Genetic Services Laboratory,University of Chicago, SCV000594089.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From GenomeConnect, ClinGen, SCV000607274.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedphenotyping onlynot provided

Description

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Johns Hopkins Genomics, Johns Hopkins University, SCV000864219.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Equipe Genetique des Anomalies du Developpement, Université de Bourgogne, SCV000883108.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot providednot providednot providednot providednot provided

From Mendelics, SCV000886152.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot providednot providednot providednot providednot provided

From Department of Genetics,Sultan Qaboos University Hospital, Oman, SCV000891676.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot providednot providednot providednot providednot provided

From Institute of Human Genetics, Klinikum rechts der Isar, SCV001149705.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1inheritedyes1bloodnot provided1not providednot providednot provided

From Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics, SCV001161676.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1Indian Hindu1not providednot providedclinical testing PubMed (1)

Description

A homozygous 3 base pair deletion in exon 11 of the CFTR gene that results in the in-frame deletion of Phenylalanine was detected. The observed variant c.1521_1523del (p.Phe508del) has a minor allele frequency of 0.4% and 0.68% in the 1000 Genomes and ExAC databases respectively. The observed variation has previously been identified in patients affected with cystic fibrosis and it lies in the ABC transporter domain of the CFTR protein (Riordan et al 1989). The in silico prediction of the variant is damaging by MutationTaster2. The reference codon is conserved across mammals. In summary, the variant meets our criteria to be classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

From CFTR-France, SCV001169465.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Myriad Women's Health, Inc., SCV001193905.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

NM_000492.3(CFTR):c.1521_1523delCTT(aka F508del) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of disease. Sources cited for classification include the following: PMID 23974870 and 15371902. Classification of NM_000492.3(CFTR):c.1521_1523delCTT(aka F508del) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Victorian Clinical Genetics Services,Murdoch Childrens Research Institute, SCV001244997.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providedyesclinical testing PubMed (1)

Description

A heterozygous inframe deletion variant, NM_000492.3(CFTR):c.1521_1523del, has been identified in exon 11 of 27 in the CFTR gene. The variant is predicted to result in an inframe deletion of a single amino acid at position 508 of the protein, NP_000483.3(CFTR):p.(Phe508del). The phenylalanine at this position has very high conservation (UCSC, 100 vertebrates), and is located in the ABC transporter 1 functional domain. This variant is present in the gnomAD database at a frequency of 0.7% (2027 heterozygotes, 1 homozygote), and has been previously reported multiple times in individuals with cystic fibrosis, being the most common causative variant in the CFTR gene (ClinVar; Egan, ME. et al. (2016)). Analysis of parental samples indicated this variant was maternally inherited. Based on information available at the time of curation, this variant has been classified as PATHOGENIC.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1maternalunknownnot providednot providednot provided2not provided1not provided

From UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill - NSIGHT-NC NEXUS, SCV001251533.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedresearch PubMed (2)

Description

The CFTR c.1521_1523delCTT (p.F508del) variant is the most common pathogenic CFTR variant (PMID: 20301428, 2233932).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenonot providednot providednot provided2not providednot providednot provided

From Centogene AG - the Rare Disease Company, SCV001424387.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Baylor Genetics, SCV001527339.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot providednot providednot providednot providednot provided

From GeneReviews, SCV001622798.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Nilou-Genome Lab, SCV001810348.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenonot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 20, 2021

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