ClinVar Genomic variation as it relates to human health
NM_033380.3(COL4A5):c.1525G>C (p.Gly509Arg)
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.1525G>C (p.Gly509Arg)
Variation ID: 988118 Accession: VCV000988118.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq22.3 X: 108597006 (GRCh38) [ NCBI UCSC ] X: 107840236 (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 22, 2021 Feb 28, 2024 May 16, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_033380.3:c.1525G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_203699.1:p.Gly509Arg missense NM_000495.5:c.1525G>C NP_000486.1:p.Gly509Arg missense NC_000023.11:g.108597006G>C NC_000023.10:g.107840236G>C NG_011977.2:g.162083G>C LRG_232:g.162083G>C LRG_232t1:c.1525G>C LRG_232p1:p.Gly509Arg LRG_232t2:c.1525G>C LRG_232p2:p.Gly509Arg - Protein change
- G509R
- Other names
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- Canonical SPDI
- NC_000023.11:108597005:G:C
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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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0.00026 (T)
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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Links
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
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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 |
2488 | 2667 |
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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Likely pathogenic (1) |
no assertion criteria provided
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May 16, 2019 | RCV001328079.1 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 30, 2021 | RCV001780226.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 16, 2023 | RCV001880181.3 |
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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Likely pathogenic
(Aug 06, 2018)
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criteria provided, single submitter
Method: clinical testing
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X-linked Alport syndrome
Affected status: yes
Allele origin:
de novo
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Center of Genomic medicine, Geneva, University Hospital of Geneva
Accession: SCV001739291.1
First in ClinVar: Dec 29, 2021 Last updated: Dec 29, 2021 |
Number of individuals with the variant: 1
Age: 0-9 years
Sex: female
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Likely pathogenic
(Oct 30, 2021)
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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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Revvity Omics, Revvity
Accession: SCV002023313.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Likely pathogenic
(May 16, 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: SCV002309101.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 28, 2024 |
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more)
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Gly509 amino acid residue in COL4A5. Other variant(s) that disrupt this residue have been observed in individuals with COL4A5-related conditions (PMID: 24304881), which suggests that this may be a clinically significant amino acid residue. This variant disrupts the triple helix domain of COL4A5. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL4A5, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 23720012, 27627812) compared to the general population (ExAC). Experimental studies have shown that this missense change affects COL4A5 function (PMID: 32405592). 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) performed at Invitae indicates that this missense variant is expected to disrupt COL4A5 protein function. ClinVar contains an entry for this variant (Variation ID: 988118). This missense change has been observed in individual(s) with COL4A5-related conditions (PMID: 32405592, 34440452). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 509 of the COL4A5 protein (p.Gly509Arg). (less)
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Likely pathogenic
(May 16, 2019)
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no assertion criteria provided
Method: clinical testing
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Alport syndrome
Affected status: yes
Allele origin:
unknown
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Sydney Genome Diagnostics, Children's Hospital Westmead
Accession: SCV001449301.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This individual is heterozygous for the c.1525G>C variant in the COL4A5 gene, which results in the amino acid substitution of glycine to arginine at residue … (more)
This individual is heterozygous for the c.1525G>C variant in the COL4A5 gene, which results in the amino acid substitution of glycine to arginine at residue 509, p.(Gly509Arg). To our knowledge, the variant has not been reported in any population databases (i.e. gnomAD, ExAC, ESP or dbSNP), and also has not been reported in the literature or any disease specific databases. This variant results in substitution of one of the invariant glycine residues within the triple helical domain of the alpha 5 chain of type IV collagen. A difference missense variant involving the same amino acid, c.1526G>A p.(Gly509Asp), has been previously reported in 2 male siblings with end stage renal disease (Fallerini et al 2014 Clin Genet 86:252-257). This variant is considered to be likely pathogenic according to the ACMG guidelines (Evidence used: PM1_strong, PM2, PM5). (less)
Number of individuals with the variant: 1
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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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Benefits of Exome Sequencing in Children with Suspected Isolated Hearing Loss. | Van Heurck R | Genes | 2021 | PMID: 34440452 |
Trimerization and Genotype-Phenotype Correlation of COL4A5 Mutants in Alport Syndrome. | Kamura M | Kidney international reports | 2020 | PMID: 32405592 |
X-Linked and Autosomal Recessive Alport Syndrome: Pathogenic Variant Features and Further Genotype-Phenotype Correlations. | Savige J | PloS one | 2016 | PMID: 27627812 |
Milder clinical aspects of X-linked Alport syndrome in men positive for the collagen IV α5 chain. | Hashimura Y | Kidney international | 2014 | PMID: 24304881 |
DNA variant databases improve test accuracy and phenotype prediction in Alport syndrome. | International Alport Mutation Consortium | Pediatric nephrology (Berlin, Germany) | 2014 | PMID: 23720012 |
Collagen structure and stability. | Shoulders MD | Annual review of biochemistry | 2009 | PMID: 19344236 |
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 |
Crystal and molecular structure of a collagen-like peptide at 1.9 A resolution. | Bella J | Science (New York, N.Y.) | 1994 | PMID: 7695699 |
Characterization of collagen-like peptides containing interruptions in the repeating Gly-X-Y sequence. | Long CG | Biochemistry | 1993 | PMID: 8218237 |
Identification of mutations in the COL4A5 collagen gene in Alport syndrome. | Barker DF | Science (New York, N.Y.) | 1990 | PMID: 2349482 |
Text-mined citations for rs754223700 ...
HelpRecord last updated Mar 17, 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.