Submissions for variant NM_033380.3(COL4A5):c.2998G>A (p.Gly1000Arg)

gnomAD frequency: 0.00003  dbSNP: rs2067110688

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001377309	SCV001574611	likely pathogenic	not provided	2024-01-05	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 1000 of the COL4A5 protein (p.Gly1000Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Alport syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 1066338). 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). This variant disrupts the p.Gly1000 amino acid residue in COL4A5. Other variant(s) that disrupt this residue have been observed in individuals with COL4A5-related conditions (PMID: 29270492), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230669	SCV003929026	likely pathogenic	X-linked Alport syndrome	2025-03-03	criteria provided, single submitter	clinical testing	Variant summary: COL4A5 c.2998G>A (p.Gly1000Arg) results in a non-conservative amino acid change within the triple-helical region (UniProt) of the encoded protein sequence. This missense variant disrupts a critical glycine residue at position 1 of a Gly-X-Y repeat in the collagenous domain of the collagen IV alpha 5 chain, and variants affecting these glycine residues are significantly enriched in individuals with Alport syndrome (PMID: 33854215). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 177702 control chromosomes. c.2998G>A has been reported in the literature as an unspecified genotype in at least one individual affected with focal and segmental glomerulosclerosis who underwent WES (Wang_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31308072). ClinVar contains an entry for this variant (Variation ID: 1066338). Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV001377309	SCV004021581	likely pathogenic	not provided	2023-07-18	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Observed in hemizygous state in a patient with thin basement membrane disease, hematuria, and proteinuria referred for genetic testing at GeneDx; 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 (Jais et al., 2000); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 10752524)
Mayo Clinic Laboratories, Mayo Clinic	RCV001377309	SCV005413435	likely pathogenic	not provided	2023-06-13	criteria provided, single submitter	clinical testing	PP3, PM1, PM2, PM5
Fulgent Genetics, Fulgent Genetics	RCV003230669	SCV005674760	pathogenic	X-linked Alport syndrome	2024-01-26	criteria provided, single submitter	clinical testing