Submissions for variant NM_033380.3(COL4A5):c.874G>A (p.Gly292Arg)

dbSNP: rs104886073

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001390504	SCV001592244	pathogenic	not provided	2023-10-11	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 292 of the COL4A5 protein (p.Gly292Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked Alport syndrome (PMID: 20378821). ClinVar contains an entry for this variant (Variation ID: 1076557). 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). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics	RCV001390504	SCV002771287	pathogenic	not provided	2021-06-14	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. This variant alters a critical location within the protein, and is expected to severely affect function and cause disease.
GeneDx	RCV001390504	SCV003921603	pathogenic	not provided	2022-12-27	criteria provided, single submitter	clinical testing	Reported in a family with Alport syndrome in published literature (Bekheirnia et al., 2010); 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 (HGMD; Jais et al., 2000); 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: 20378821, 10752524)
Mayo Clinic Laboratories, Mayo Clinic	RCV001390504	SCV004227694	likely pathogenic	not provided	2022-10-13	criteria provided, single submitter	clinical testing	PP3, PM1, PM2_supporting, PS4_moderate
Fulgent Genetics, Fulgent Genetics	RCV005040269	SCV005679788	pathogenic	X-linked Alport syndrome	2024-03-12	criteria provided, single submitter	clinical testing