ClinVar Miner

Submissions for variant NM_033380.3(COL4A5):c.929G>A (p.Gly310Glu)

dbSNP: rs1556407064
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001958672 SCV002232121 pathogenic not provided 2020-11-27 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 310 of the COL4A5 protein (p.Gly310Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with X-linked Alport syndrome (PMID: 24304881, Invitae). ClinVar contains an entry for this variant (Variation ID: 587245). 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. 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). For these reasons, this variant has been classified as Pathogenic.
3billion RCV002051997 SCV002318811 likely pathogenic X-linked Alport syndrome 2022-03-22 criteria provided, single submitter clinical testing Different pathogenic/likely pathogenic amino acid change has been reported with supporting evidence at the same codon (ClinVar ID: VCV000438707, PMID:17396119). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.978>=0.6, 3CNET: 0.972>=0.75). A missense variant is a common mechanism associated with Alport syndrome 1, X-linked. It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.

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