Submissions for variant NM_033380.3(COL4A5):c.1120G>A (p.Gly374Arg)

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Total submissions: 5

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Medical Genetics, University of Parma	RCV001089921	SCV001245121	likely pathogenic	X-linked Alport syndrome	2020-03-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001862665	SCV002312095	pathogenic	not provided	2023-08-04	criteria provided, single submitter	clinical testing	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.Gly374 amino acid residue in COL4A5. Other variant(s) that disrupt this residue have been observed in individuals with COL4A5-related conditions (PMID: 30577881; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 374 of the COL4A5 protein (p.Gly374Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of X-linked COL4A5-related conditions (PMID: 30577881, 33369211). ClinVar contains an entry for this variant (Variation ID: 870363). 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.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV001089921	SCV002568255	likely pathogenic	X-linked Alport syndrome	2022-06-30	criteria provided, single submitter	clinical testing	PS4_Moderate, PM1, PM2, PM5_Supporting, PP3
3billion, Medical Genetics	RCV001089921	SCV002572820	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. It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000870363 ) and different missense changes at the same codon (p.Gly374Ala, p.Gly374Val; PMID: 30577881 , 8651296 ) have been previously reported to be associated with COL4A5--related disorder . Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics	RCV001089921	SCV002807581	pathogenic	X-linked Alport syndrome	2022-03-31	criteria provided, single submitter	clinical testing

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