Submissions for variant NM_000092.5(COL4A4):c.4901G>C (p.Cys1634Ser)

dbSNP: rs1345086570

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003026871	SCV003328323	pathogenic	not provided	2022-03-15	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 1634 of the COL4A4 protein (p.Cys1634Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant Alport syndrome (PMID: 15086897). It has also been observed to segregate with disease in related individuals. 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 COL4A4 protein function. This variant disrupts the p.Cys1634 amino acid residue in COL4A4. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004765627	SCV005380835	uncertain significance	not specified	2024-08-08	criteria provided, single submitter	clinical testing	Variant summary: COL4A4 c.4901G>C (p.Cys1634Ser) results in a non-conservative amino acid change located in the Collagen IV, non-collagenous domain (IPR001442) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249150 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4901G>C in individuals affected with Alport Syndrome, Autosomal Recessive and no experimental evidence demonstrating its impact on protein function have been reported, although a different variant resulting in the same missense change was found in individuals with Autosomal-dominant Alport syndrome (PMID 15086897). ClinVar contains an entry for this variant (Variation ID: 2112525). Based on the evidence outlined above, the variant was classified as uncertain significance.