ClinVar Genomic variation as it relates to human health
NM_033380.3(COL4A5):c.5048G>A (p.Arg1683Gln)
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_033380.3(COL4A5):c.5048G>A (p.Arg1683Gln)
Variation ID: 10467 Accession: VCV000010467.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq22.3 X: 108696350 (GRCh38) [ NCBI UCSC ] X: 107939580 (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 Apr 4, 2013 Mar 16, 2024 Feb 9, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_033380.3:c.5048G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_203699.1:p.Arg1683Gln missense NM_000495.5:c.5030G>A NP_000486.1:p.Arg1677Gln missense NM_033380.2:c.5048G>A NC_000023.11:g.108696350G>A NC_000023.10:g.107939580G>A NG_011977.2:g.261427G>A LRG_232:g.261427G>A LRG_232t1:c.5030G>A LRG_232p1:p.Arg1677Gln LRG_232t2:c.5048G>A LRG_232p2:p.Arg1683Gln P29400:p.Arg1677Gln - Protein change
- R1677Q, R1683Q
- Other names
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- Canonical SPDI
- NC_000023.11:108696349: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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00002
Exome Aggregation Consortium (ExAC) 0.00002
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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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COL4A5 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2500 | 2679 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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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Pathogenic/Likely pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Sep 2, 2022 | RCV000011213.18 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Nov 24, 2023 | RCV000518046.12 | |
Pathogenic (1) |
no assertion criteria provided
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May 30, 2018 | RCV001328066.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 9, 2024 | RCV003934823.1 |
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
Help
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
Help
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
Help
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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Pathogenic
(Sep 16, 2018)
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criteria provided, single submitter
Method: research
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not provided
Affected status: yes
Allele origin:
germline
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Gharavi Laboratory, Columbia University
Accession: SCV000809274.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
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Pathogenic
(Jan 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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X-linked Alport syndrome
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001439915.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
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Likely pathogenic
(Oct 20, 2021)
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criteria provided, single submitter
Method: clinical testing
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X-linked Alport syndrome
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002580335.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS4_MOD, PM1, PM5, PS3_SUP, PM2_SUP, PP3, PP4
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Number of individuals with the variant: 1
Sex: female
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Pathogenic
(Feb 09, 2024)
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criteria provided, single submitter
Method: clinical testing
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COL4A5-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004750581.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The COL4A5 c.5030G>A variant is predicted to result in the amino acid substitution p.Arg1677Gln. This variant was reported in three independent Ashkenazi-American families with features … (more)
The COL4A5 c.5030G>A variant is predicted to result in the amino acid substitution p.Arg1677Gln. This variant was reported in three independent Ashkenazi-American families with features of COL4A5-related disorders (Barker et al. 1997. PubMed ID: 9150741; Pont-Kingdon et al. 2009. PubMed ID: 19919694). This variant was also reported in a 57 year old female patient with mild chronic kidney disease (Table 2 in Lata et al. 2017. PubMed ID: 29204651) and in a male patient with nephrosclerosis and deafness and his mother with deafness (Ottlewski et al. 2019. PubMed ID: 31027891). This variant is reported in 0.040% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic. (less)
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Likely pathogenic
(Dec 11, 2018)
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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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Athena Diagnostics
Accession: SCV000612999.3
First in ClinVar: Dec 19, 2017 Last updated: Jan 19, 2020 |
Comment:
Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the … (more)
Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Damaging to protein function(s) relevant to disease mechanism. (less)
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Pathogenic
(Apr 08, 2021)
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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: SCV001796427.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Comment:
Published functional studies demonstrate R1683Q results in a loss of formation of the type IV collagen heterotrimers (Kobayashi et al., 2008); In silico analysis, which … (more)
Published functional studies demonstrate R1683Q results in a loss of formation of the type IV collagen heterotrimers (Kobayashi et al., 2008); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 19919694, 20378821, 9150741, 29144512, 29204651, 29526710, 18083113) (less)
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Pathogenic
(Feb 18, 2022)
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criteria provided, single submitter
Method: clinical testing
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X-linked Alport syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002103517.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
Comment:
Variant summary: COL4A5 c.5030G>A (p.Arg1677Gln) results in a conservative amino acid change located in the Collagen IV, non-collagenous domain of the encoded protein sequence. Four … (more)
Variant summary: COL4A5 c.5030G>A (p.Arg1677Gln) results in a conservative amino acid change located in the Collagen IV, non-collagenous domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.2e-05 in 183310 control chromosomes. c.5030G>A has been reported in the literature in multiple individuals affected with Alport Syndrome 1, X-Linked Recessive or Nephrosclerosis/deafness (e.g. Bekheirnia_2010, Ottlewski_2019). These data indicate that the variant is very likely to be associated with disease. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Sep 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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X-linked Alport syndrome
(X-linked dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767563.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with X-linked Alport syndrome 1 (MIM#301050). Dominant negative is caused mostly glycine substitutions that affect the conformation of the protein, and loss of function can be caused by either protein truncating or missense variants (PMID: 24046192, PMID: 12028435). (I) 0110 - This gene is known to be associated with X-linked dominant disease. Males are typically more severely affected than females (PMID: 19965530). (I) 0115 - Variants in this gene are known to have variable expressivity. There is intrafamilial variability among affected carrier females, possibly due to variable X-inactivation (PMID: 14514738). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0253 - Variant is hemizygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (4 heterozygotes, 0 homozygotes, 0 hemizygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the C-terminal tandem repeated domain in type 4 collagen (NCBI conserved domain). (I) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. The p.(Arg1677Pro) and p.(Arg1677Leu) comparable variants have each been reported in an individual with Alport Syndrome, respectively (PMIDs: 11223851; 21505094). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is an Ashkenazi Jewish founder mutation and has been classified as pathogenic in ClinVar (PMIDs: 9150741; 27627812). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. HEK293T cells carrying the p.(Arg1683Gln) mutant construct demonstrated impaired trimer formation ability with alpha-3 and alpha-4 collagen chains compared with the wild type construct (PMID: 29526710). (SP) 1102 - Strong phenotype match. (SP) 1208 - Inheritance information for this variant is not currently available. (I) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less)
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Pathogenic
(Feb 06, 2022)
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criteria provided, single submitter
Method: clinical testing
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X-linked Alport syndrome
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV001752777.2
First in ClinVar: Jul 18, 2021 Last updated: Dec 31, 2022 |
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Pathogenic
(Nov 24, 2023)
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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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Invitae
Accession: SCV000961772.6
First in ClinVar: Aug 13, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1677 of the COL4A5 protein (p.Arg1677Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1677 of the COL4A5 protein (p.Arg1677Gln). This variant is present in population databases (rs104886308, gnomAD 0.04%). This missense change has been observed in individuals with adult-onset Alport syndrome (PMID: 9150741, 19919694, 20378821). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 10467). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL4A5 protein function. Experimental studies have shown that this missense change affects COL4A5 function (PMID: 18083113). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 01, 2003)
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no assertion criteria provided
Method: literature only
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ALPORT SYNDROME 1, X-LINKED
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000031440.3
First in ClinVar: Apr 04, 2013 Last updated: Feb 04, 2019 |
Comment on evidence:
Nearly all cases of Alport syndrome (ALS1; 301050) involve distinct mutations, as expected for an X-linked disease that significantly reduces the fitness of affected males. … (more)
Nearly all cases of Alport syndrome (ALS1; 301050) involve distinct mutations, as expected for an X-linked disease that significantly reduces the fitness of affected males. A few COL4A5 mutations appear to be associated with reduced disease severity and may account for an appreciable proportion of late-onset Alport syndrome in populations where a founder effect has occurred. Barker et al. (1997) reported a novel mutation in the COL4A5 gene, R1677Q. It was detected in 3 independently ascertained Ashkenazi-American families, caused a relatively mild form of nephritis with typical onset in the fourth or fifth decade, and may be involved in the etiology of a large proportion of adult-onset hereditary nephritis in Ashkenazi Jews. The mutation was a G-to-A transition in nucleotide 5232 and represented a change at a CpG dinucleotide. The same haplotype of COL4A5-linked markers was found in affected males of the 3 kindreds. No genealogic connection could be established. Ohkubo et al. (2003) found immunohistochemical evidence that the normal anterior lens capsule expressed all of the A4 collagen chains. They also examined the anterior lens capsule of a patient with Alport syndrome due to the R1677X nonsense mutation. The patient's anterior lenticonus resulted in a lack of immunoreactivity to 4A3 to 4A6 chains in the anterior lens capsule. (less)
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Pathogenic
(Feb 13, 2019)
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no assertion criteria provided
Method: clinical testing
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X-linked Alport syndrome
Affected status: yes
Allele origin:
germline
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Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare
Accession: SCV000925849.1
First in ClinVar: Jul 14, 2019 Last updated: Jul 14, 2019 |
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Pathogenic
(May 30, 2018)
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no assertion criteria provided
Method: clinical testing
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Hematuria
Affected status: yes
Allele origin:
unknown
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Sydney Genome Diagnostics, Children's Hospital Westmead
Accession: SCV001449288.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This patient is heterozygous for a known pathogenic variant, c.5030G>A (p.Arg1677Gln), in the COL4A5 gene. This variant (dbSNP: rs104886308), located in the C terminal domain … (more)
This patient is heterozygous for a known pathogenic variant, c.5030G>A (p.Arg1677Gln), in the COL4A5 gene. This variant (dbSNP: rs104886308), located in the C terminal domain of COL4A5, has been previously reported in numerous patients with adult-onset X-linked Alport syndrome in the literature (Barker et al 1997 Hum Genet 99:681-684; Pont-Kingdon et al 2009 BMC Nephrol 10:38; Bekheirnia et al 2010 J Am Soc Nephrol 21:876-883). (less)
Number of individuals with the variant: 1
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not provided
(-)
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no classification provided
Method: literature only
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X-linked Alport syndrome
Affected status: not provided
Allele origin:
unknown
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GeneReviews
Accession: SCV000057826.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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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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Value of renal gene panel diagnostics in adults waiting for kidney transplantation due to undetermined end-stage renal disease. | Ottlewski I | Kidney international | 2019 | PMID: 31027891 |
Alport Syndrome. | Adam MP | - | 2019 | PMID: 20301386 |
A Split-Luciferase-Based Trimer Formation Assay as a High-throughput Screening Platform for Therapeutics in Alport Syndrome. | Omachi K | Cell chemical biology | 2018 | PMID: 29526710 |
Ashkenazi Jewish genomic variants: integrating data from the Israeli National Genetic Database and gnomAD. | Zlotogora J | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29144512 |
X-Linked and Autosomal Recessive Alport Syndrome: Pathogenic Variant Features and Further Genotype-Phenotype Correlations. | Savige J | PloS one | 2016 | PMID: 27627812 |
Molecular genetics of familial hematuric diseases. | Deltas C | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2013 | PMID: 24046192 |
Linkage analysis and a novel COL4A5 mutation in a large Turkish family with Alport syndrome. | Tug E | Genetic counseling (Geneva, Switzerland) | 2011 | PMID: 21848006 |
Twenty-one novel mutations identified in the COL4A5 gene in Chinese patients with X-linked Alport's syndrome confirmed by skin biopsy. | Ma J | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2011 | PMID: 21505094 |
Genotype-phenotype correlation in X-linked Alport syndrome. | Bekheirnia MR | Journal of the American Society of Nephrology : JASN | 2010 | PMID: 20378821 |
Mutant-type alpha5(IV) collagen in a mild form of Alport syndrome has residual ability to form a heterotrimer. | Kobayashi T | Pediatric nephrology (Berlin, Germany) | 2010 | PMID: 20130921 |
Alport retinopathy results from "severe" COL4A5 mutations and predicts early renal failure. | Tan R | Clinical journal of the American Society of Nephrology : CJASN | 2010 | PMID: 19965530 |
Molecular testing for adult type Alport syndrome. | Pont-Kingdon G | BMC nephrology | 2009 | PMID: 19919694 |
Mutational analysis of type IV collagen alpha5 chain, with respect to heterotrimer formation. | Kobayashi T | Biochemical and biophysical research communications | 2008 | PMID: 18083113 |
The genetic bases for syndromic and nonsyndromic deafness among Jews. | Ben-Yosef T | Trends in molecular medicine | 2003 | PMID: 14604828 |
X-linked Alport syndrome: natural history and genotype-phenotype correlations in girls and women belonging to 195 families: a "European Community Alport Syndrome Concerted Action" study. | Jais JP | Journal of the American Society of Nephrology : JASN | 2003 | PMID: 14514738 |
Immunohistochemical and molecular genetic evidence for type IV collagen alpha5 chain abnormality in the anterior lenticonus associated with Alport syndrome. | Ohkubo S | Archives of ophthalmology (Chicago, Ill. : 1960) | 2003 | PMID: 12796257 |
COL4A3/COL4A4 mutations: from familial hematuria to autosomal-dominant or recessive Alport syndrome. | Longo I | Kidney international | 2002 | PMID: 12028435 |
Efficient detection of Alport syndrome COL4A5 mutations with multiplex genomic PCR-SSCP. | Barker DF | American journal of medical genetics | 2001 | PMID: 11223851 |
Common ancestry of three Ashkenazi-American families with Alport syndrome and COL4A5 R1677Q. | Barker DF | Human genetics | 1997 | PMID: 9150741 |
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Text-mined citations for rs104886308 ...
HelpRecord last updated May 12, 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.