ClinVar Genomic variation as it relates to human health
NM_000492.4(CFTR):c.1270G>A (p.Gly424Ser)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000492.4(CFTR):c.1270G>A (p.Gly424Ser)
Variation ID: 286406 Accession: VCV000286406.29
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q31.2 7: 117548701 (GRCh38) [ NCBI UCSC ] 7: 117188755 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 17, 2018 May 1, 2024 Jan 17, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000492.4:c.1270G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000483.3:p.Gly424Ser missense NC_000007.14:g.117548701G>A NC_000007.13:g.117188755G>A NG_016465.4:g.87918G>A LRG_663:g.87918G>A LRG_663t1:c.1270G>A LRG_663p1:p.Gly424Ser - Protein change
- G424S
- Other names
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- Canonical SPDI
- NC_000007.14:117548700:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00009
Trans-Omics for Precision Medicine (TOPMed) 0.00009
Exome Aggregation Consortium (ExAC) 0.00010
The Genome Aggregation Database (gnomAD) 0.00012
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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CFTR | - | - |
GRCh38 GRCh37 |
3704 | 5025 | |
CFTR-AS1 | - | - | - | GRCh38 | - | 490 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jun 14, 2023 | RCV000397807.15 | |
Uncertain significance (6) |
criteria provided, multiple submitters, no conflicts
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Jan 17, 2024 | RCV000462099.19 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jun 2, 2022 | RCV000590109.21 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 25, 2022 | RCV002480028.8 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Jan 16, 2018)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000797213.1
First in ClinVar: May 26, 2018 Last updated: May 26, 2018 |
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Uncertain significance
(Mar 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000339832.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Uncertain significance
(Jul 03, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000883573.1
First in ClinVar: Dec 15, 2018 Last updated: Dec 15, 2018 |
Comment:
The CFTR c.1270G>A; p.Gly424Ser variant (rs371107552) has been reported in two individuals from a family with rheumatoid arthritis and bronchiectasis (Puechal 2011), and reported to … (more)
The CFTR c.1270G>A; p.Gly424Ser variant (rs371107552) has been reported in two individuals from a family with rheumatoid arthritis and bronchiectasis (Puechal 2011), and reported to cause exon 9 skipping in a portion of transcripts (Pagani 2003, Aissat 2013). However, this variant occurs in a weakly conserved amino acid (Chen 2001), and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be tolerated. This variant is reported in the ClinVar database as uncertain (Variation ID: 286406), and observed in general population databases with overall allele frequencies of 0.015 percent (2/12966 alleles, Exome Variant Server), and 0.008 percent (21/272812 alleles, Genome Aggregation Database), but is considered a low confidence variant in the database due to segmental duplication. Based on the above information, the clinical significance of p.Gly424Ser is uncertain at this time. REFERENCES Link to ClinVar database for p.Gly424Ser: https://0-www-ncbi-nlm-nih-gov.brum.beds.ac.uk/clinvar/variation/286406/ Aissat A et al. Combined computational-experimental analyses of CFTR exon strength uncover predictability of exon-skipping level. Hum Mutat. 2013 Jun;34(6):873-81. Chen JM et al. A combined analysis of the cystic fibrosis transmembrane conductance regulator: implications for structure and disease models. Mol Biol Evol. 2001 Sep;18(9):1771-88. Pagani F et al. Missense, nonsense, and neutral mutations define juxtaposed regulatory elements of splicing in cystic fibrosis transmembrane regulator exon 9. J Biol Chem. 2003 Jul 18;278(29):26580-8. Puechal X et al. Mutations of the cystic fibrosis gene in patients with bronchiectasis associated with rheumatoid arthritis. Ann Rheum Dis. 2011 Apr;70(4):653-9. (less)
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Uncertain significance
(May 20, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000711288.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The p.Gly424Ser variant in CFTR has been reported in at least 1 Caucasian indivi dual with diffuse bronchiectasis and rheumatoid arthritis. Multiple members of t … (more)
The p.Gly424Ser variant in CFTR has been reported in at least 1 Caucasian indivi dual with diffuse bronchiectasis and rheumatoid arthritis. Multiple members of t his family are reported to be affected, but this variant does not segregate with disease (Puechal 2011). This variant has been identified in 9/57094 European ch romosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EV S/; dbSNP rs371107552). Computational prediction tools and conservation analysis suggest that the p.Gly424Ser variant may not impact the protein, though this in formation is not predictive enough to rule out pathogenicity. In summary, the cl inical significance of the p.Gly424Ser variant is uncertain. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Oct 19, 2019)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
germline
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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV001167237.1
First in ClinVar: Mar 08, 2020 Last updated: Mar 08, 2020 |
Comment:
This CFTR variant (rs371107552) is rare (<0.1%) in large population datasets1,2 (gnomAD: 24/277606 total alleles; 0.0087%, no homozygotes). Six submitters in ClinVar classify the clinical … (more)
This CFTR variant (rs371107552) is rare (<0.1%) in large population datasets1,2 (gnomAD: 24/277606 total alleles; 0.0087%, no homozygotes). Six submitters in ClinVar classify the clinical significance of this variant as uncertain. One study has demonstrated that CFTR c.1270G>A may decrease inclusion of exon 10 (legacy exon 9) during splicing; however, bioinformatics tools do not predict this variant will alter typical splicing patterns. Two bioinformatics tools predict this amino acid substitution will be tolerated. The glycine residue at this position is not well conserved across species assessed. Due to insufficient evidence, we consider the clinical significance of c.1270G>A uncertain at this time. (less)
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Uncertain significance
(Apr 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000552133.6
First in ClinVar: Apr 17, 2017 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 424 of the CFTR protein (p.Gly424Ser). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 424 of the CFTR protein (p.Gly424Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with rheumatoid arthritis and bronchiectasis (PMID: 21131649). ClinVar contains an entry for this variant (Variation ID: 286406). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CFTR function (PMID: 12732620). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Jun 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696833.3
First in ClinVar: Mar 17, 2018 Last updated: Jul 29, 2023 |
Comment:
Variant summary: CFTR c.1270G>A (p.Gly424Ser) results in a non-conservative amino acid change located in the ABC transporter-like domain (IPR003439) of the encoded protein sequence. Three … (more)
Variant summary: CFTR c.1270G>A (p.Gly424Ser) results in a non-conservative amino acid change located in the ABC transporter-like domain (IPR003439) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, the variant resulted in reduced inclusion of exon 9 in a mini-gene assay (Pagani_2003). The variant allele was found at a frequency of 9.7e-05 in 247386 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Non-Classic Cystic Fibrosis (9.7e-05 vs 0.013), allowing no conclusion about variant significance. c.1270G>A has been reported in two affected patients with rheumatoid arthritis and diffuse bronchiectasis (RA-DB) from one family (Puechal_2011) without strong evidence for pathogenicity. The Sickkids database also reports a female patient with bronchiectasis harboring this variant. The variant has also been reported in two patients with pancreatic cancer (Tamura_2018), and in a large Cystic Fibrosis patient cohort (Raraigh_2022). These reports do not provide unequivocal conclusions about association of the variant with Non-Classic Cystic Fibrosis. The following publications have been ascertained in the context of this evaluation (PMID: 23420618, 11504857, 28603918, 15536480, 12732620, 16251901, 21131649, 25735457, 29669919, 34782259). Eleven ClinVar submitters have assessed the variant since 2014: all submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Jan 17, 2024)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV001170885.4
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The p.G424S variant (also known as c.1270G>A), located in coding exon 10 of the CFTR gene, results from a G to A substitution at nucleotide … (more)
The p.G424S variant (also known as c.1270G>A), located in coding exon 10 of the CFTR gene, results from a G to A substitution at nucleotide position 1270. The glycine at codon 424 is replaced by serine, an amino acid with similar properties. This alteration was reported in two related individuals with diffuse bronchiectasis and rheumatoid arthritis; one of the individuals also carried the p.G576A alteration but the phase was unclear (Puéchal X. et al., Ann. Rheum. Dis. 2011 Apr; 70(4):653-9). One study of Hep3B cells transfected with this alteration showed some mRNA transcripts with skipping of exon 9 in addition to wild type mRNA transcripts (Pagani F et al., J. Biol. Chem. 2003 Jul; 278(29):26580-8). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Sep 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002027397.1
First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021 |
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Uncertain significance
(Jun 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002759167.1
First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022 |
Comment:
Identified in the single heterozygous state or with a second CFTR variant, phase unknown, in an asymptomatic individual and individuals with bronchiectasis (Puchal et al., … (more)
Identified in the single heterozygous state or with a second CFTR variant, phase unknown, in an asymptomatic individual and individuals with bronchiectasis (Puchal et al., 2011; Claustres et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25735457, 12732620, 11504857, 23420618, 21131649, 29669919, 15536480, 16251901, 28603918) (less)
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Uncertain significance
(May 25, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary pancreatitis
Bronchiectasis with or without elevated sweat chloride 1 Cystic fibrosis Congenital bilateral aplasia of vas deferens from CFTR mutation
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002786365.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Cystic Fibrosis
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001456066.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Complete CFTR gene sequencing in 5,058 individuals with cystic fibrosis informs variant-specific treatment. | Raraigh KS | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2022 | PMID: 34782259 |
Mutations in the pancreatic secretory enzymes CPA1 and CPB1 are associated with pancreatic cancer. | Tamura K | Proceedings of the National Academy of Sciences of the United States of America | 2018 | PMID: 29669919 |
CFTR-France, a national relational patient database for sharing genetic and phenotypic data associated with rare CFTR variants. | Claustres M | Human mutation | 2017 | PMID: 28603918 |
Comparative ex vivo, in vitro and in silico analyses of a CFTR splicing mutation: Importance of functional studies to establish disease liability of mutations. | Ramalho AS | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2016 | PMID: 25735457 |
Combined computational-experimental analyses of CFTR exon strength uncover predictability of exon-skipping level. | Aissat A | Human mutation | 2013 | PMID: 23420618 |
Mutations of the cystic fibrosis gene in patients with bronchiectasis associated with rheumatoid arthritis. | Puéchal X | Annals of the rheumatic diseases | 2011 | PMID: 21131649 |
Haplotype block structure study of the CFTR gene. Most variants are associated with the M470 allele in several European populations. | Pompei F | European journal of human genetics : EJHG | 2006 | PMID: 16251901 |
A large-scale study of the random variability of a coding sequence: a study on the CFTR gene. | Modiano G | European journal of human genetics : EJHG | 2005 | PMID: 15536480 |
Missense, nonsense, and neutral mutations define juxtaposed regulatory elements of splicing in cystic fibrosis transmembrane regulator exon 9. | Pagani F | The Journal of biological chemistry | 2003 | PMID: 12732620 |
A combined analysis of the cystic fibrosis transmembrane conductance regulator: implications for structure and disease models. | Chen JM | Molecular biology and evolution | 2001 | PMID: 11504857 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR | - | - | - | - |
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Text-mined citations for rs371107552 ...
HelpRecord last updated Jun 10, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.