ClinVar Miner

Submissions for variant NM_001845.6(COL4A1):c.1022G>C (p.Gly341Ala)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002617695 SCV002955576 likely pathogenic not provided 2022-11-07 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 341 of the COL4A1 protein (p.Gly341Ala). This variant is not present in population databases (gnomAD no frequency). 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 not expected to disrupt COL4A1 protein function. This variant has not been reported in the literature in individuals affected with COL4A1-related conditions. 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. This variant disrupts the triple helix domain of COL4A1. 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 COL4A1 variants affecting these glycine residues are significantly enriched in individuals with disease (PMID: 9016532, 17078022) compared to the general population (ExAC).
Fulgent Genetics, Fulgent Genetics RCV005002854 SCV005632461 likely pathogenic Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome; Brain small vessel disease 1 with or without ocular anomalies; Hemorrhage, intracerebral, susceptibility to; Retinal arterial tortuosity; Microangiopathy and leukoencephalopathy, pontine, autosomal dominant 2024-03-28 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004725327 SCV005336278 likely pathogenic COL4A1-related disorder 2024-08-16 no assertion criteria provided clinical testing The COL4A1 c.1022G>C variant is predicted to result in the amino acid substitution p.Gly341Ala. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. This variant impacts a glycine (Gly) residue within the highly conserved collagen triple helical domain (Gly-X-Y; amino acids 173-1440) where Gly substitutions are expected to be pathogenic (https://www.uniprot.org/; https://www.ncbi.nlm.nih.gov/books/NBK7046/). This variant is interpreted as likely pathogenic.

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