Submissions for variant NM_033380.3(COL4A5):c.2732G>A (p.Gly911Glu)

dbSNP: rs104886363

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
3billion	RCV002283810	SCV002572913	likely pathogenic	X-linked Alport syndrome	2022-09-01	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.99; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with COL4A5 -related disorder (PMID: 10684360). A different missense change at the same codon (p.Gly911Arg) has been reported to be associated with COL4A5 -related disorder (PMID: 29204651). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
PreventionGenetics, part of Exact Sciences	RCV003395444	SCV004120060	pathogenic	COL4A5-related disorder	2023-06-26	criteria provided, single submitter	clinical testing	The COL4A5 c.2732G>A variant is predicted to result in the amino acid substitution p.Gly911Glu. This variant was reported in an individual with Alport syndrome and was reported to occur de novo in a female patient with features of a COL4A5-related disorder (Cheong et al. 2000. PubMed ID: 10684360; Yokota et al. 2016. PubMed ID: 27796712). At PreventionGenetics, we have observed the c.2732G>A variant in an individual with kidney disease (internal data). The p.Gly911Glu variant affects a Gly residue of the conserved triple helical domain, where substitutions of the glycine are usually pathogenic (Hudson et al. 1993. PubMed ID: 8253711; https://www.ncbi.nlm.nih.gov/books/NBK21582/). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005096038	SCV005841067	pathogenic	not provided	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 911 of the COL4A5 protein (p.Gly911Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Alport syndrome (PMID: 10684360; Invitae). ClinVar contains an entry for this variant (Variation ID: 1705496). 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 with a positive predictive value of 95%. 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). For these reasons, this variant has been classified as Pathogenic.