Submissions for variant NM_000091.5(COL4A3):c.4994G>A (p.Cys1665Tyr)

gnomAD frequency: 0.00003  dbSNP: rs376550779

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514326	SCV000609552	likely pathogenic	not provided	2017-03-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000514326	SCV002307030	pathogenic	not provided	2024-03-07	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1665 of the COL4A3 protein (p.Cys1665Tyr). This variant is present in population databases (rs376550779, gnomAD 0.008%). This missense change has been observed in individual(s) with autosomal recessive Alport syndrome (PMID: 24052634; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 445315). 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 COL4A3 protein function with a positive predictive value of 80%. This variant disrupts the p.Cys1665 amino acid residue in COL4A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24052634; 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004787818	SCV005399695	uncertain significance	Alport syndrome	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with Alport syndrome, MONDO:0018965, COL4A3-related. Glycine changes that are part of a G-X-Y repeat in the triple helix of a collagen domain are known to have a dominant negative effect (PMID: 12028435). (I) 0108 - This gene is associated with both recessive (Alport syndrome 2 MIM#203780) and dominant disease (Alport syndrome 3 MIM#104200) (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to tyrosine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (12 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated C-terminal tandem repeated domain in type 4 procollagen domain, and is involved in a disulphide bond (DECIPHER). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Cys1665Ser) has been classified as likely pathogenic by a clinical laboratory in ClinVar who observed the variant in an individual with autosomal recessive Alport syndrome. (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic, pathogenic, or a VUS by clinical laboratories in Clinvar, one of whom observed the variant in an individual with autosomal recessive Alport syndrome. This variant has also been observed in two individuals with Alport syndrome in the literature, once as likely compound heterozygous and once in an individual who also had a COL4A4 missense variant (PMIDs: 24052634, 25575550). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Counsyl	RCV000673499	SCV000798707	uncertain significance	Autosomal recessive Alport syndrome	2018-03-20	flagged submission	clinical testing