ClinVar Miner

Submissions for variant NM_033380.3(COL4A5):c.2696G>A (p.Gly899Asp)

dbSNP: rs281874702
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000710870 SCV000603149 likely pathogenic not provided 2017-05-11 criteria provided, single submitter clinical testing 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.
Athena Diagnostics RCV000710870 SCV000841177 pathogenic not provided 2017-08-25 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000710870 SCV002257785 likely pathogenic not provided 2021-09-14 criteria provided, single submitter clinical testing 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. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with clinical features of Alport syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 439521). 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 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). 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. 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.
Fulgent Genetics, Fulgent Genetics RCV005049578 SCV005674751 likely pathogenic X-linked Alport syndrome 2024-02-05 criteria provided, single submitter clinical testing

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