ClinVar Miner

Submissions for variant NM_033380.3(COL4A5):c.1414G>A (p.Gly472Arg)

dbSNP: rs104886116
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001387022 SCV001587511 pathogenic not provided 2023-03-08 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. 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 sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 472 of the COL4A5 protein (p.Gly472Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Alport syndrome (PMID: 94548, 10872188). ClinVar contains an entry for this variant (Variation ID: 24408). 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.
GeneDx RCV001387022 SCV005201627 pathogenic not provided 2024-01-17 criteria provided, single submitter clinical testing Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A5 gene, where the majority of pathogenic missense variants occur, and is predicted to disrupt normal protein folding and function (PMID: 10752524); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25525159, 10752524, 10872188, 10094548)
Fulgent Genetics, Fulgent Genetics RCV005042078 SCV005674673 pathogenic X-linked Alport syndrome 2024-05-07 criteria provided, single submitter clinical testing

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