ClinVar Genomic variation as it relates to human health
NM_033380.3(COL4A5):c.2696G>A (p.Gly899Asp)
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.2696G>A (p.Gly899Asp)
Variation ID: 439521 Accession: VCV000439521.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq22.3 X: 108621821 (GRCh38) [ NCBI UCSC ] X: 107865051 (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 Oct 20, 2018 Feb 20, 2024 Sep 14, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_033380.3:c.2696G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_203699.1:p.Gly899Asp missense NM_000495.5:c.2696G>A NP_000486.1:p.Gly899Asp missense NC_000023.11:g.108621821G>A NC_000023.10:g.107865051G>A NG_011977.2:g.186898G>A LRG_232:g.186898G>A LRG_232t1:c.2696G>A LRG_232p1:p.Gly899Asp LRG_232t2:c.2696G>A LRG_232p2:p.Gly899Asp - Protein change
- G899D
- Other names
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- Canonical SPDI
- NC_000023.11:108621820: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.
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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 |
2599 | 2780 |
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
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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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Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Sep 14, 2021 | RCV000710870.14 |
Submissions - Germline
Classification
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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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Pathogenic
(Aug 25, 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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Athena Diagnostics
Accession: SCV000841177.1
First in ClinVar: Oct 20, 2018 Last updated: Oct 20, 2018 |
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Likely pathogenic
(May 11, 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: SCV000603149.2
First in ClinVar: Sep 30, 2017 Last updated: Feb 17, 2019 |
Comment:
The COL4A5 c.2696G>A, p.Gly899Asp variant has not been reported in the medical literature, listed in gene-specific variant databases or the ClinVar database, nor observed in … (more)
The COL4A5 c.2696G>A, p.Gly899Asp variant has not been reported in the medical literature, listed in gene-specific variant databases or the ClinVar database, nor observed in the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). However, another missense at this residue (p.Gly899Val) has been implicated in Alport syndrome (Ma 2011). The glycine at residue 899 is highly conserved, and lies in the collagen triple-helix repeat domain. Computational algorithms (Mutation Taster, PolyPhen-2, SIFT) predict that the variant has an impact on the protein. Based on the above information, the variant is classified as likely pathogenic. References: Ma J et al. Twenty-one novel mutations identified in the COL4A5 gene in Chinese patients with X-linked Alport's syndrome confirmed by skin biopsy. Nephrol Dial Transplant. 2011 26(12):4003-10. (less)
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Likely pathogenic
(Sep 14, 2021)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002257785.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 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.Gly899 amino acid residue in COL4A5. Other variant(s) that disrupt this residue have been observed in individuals with COL4A5-related conditions (PMID: 21505094), 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). 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. This sequence change replaces glycine with aspartic acid at codon 899 of the COL4A5 protein (p.Gly899Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. ClinVar contains an entry for this variant (Variation ID: 439521). This missense change has been observed in individual(s) with clinical features of Alport syndrome (Invitae). This variant is not present in population databases (ExAC no frequency). (less)
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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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X-Linked and Autosomal Recessive Alport Syndrome: Pathogenic Variant Features and Further Genotype-Phenotype Correlations. | Savige J | PloS one | 2016 | PMID: 27627812 |
DNA variant databases improve test accuracy and phenotype prediction in Alport syndrome. | International Alport Mutation Consortium | Pediatric nephrology (Berlin, Germany) | 2014 | PMID: 23720012 |
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 |
Collagen structure and stability. | Shoulders MD | Annual review of biochemistry | 2009 | PMID: 19344236 |
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 |
Text-mined citations for rs281874702 ...
HelpRecord last updated Sep 29, 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.