ClinVar Miner

Submissions for variant NM_001845.6(COL4A1):c.1076G>T (p.Gly359Val)

dbSNP: rs2501568764
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Gemeinschaftspraxis fuer Humangenetik Dresden RCV003493321 SCV004239205 likely pathogenic Brain small vessel disease 1 with or without ocular anomalies 2023-07-17 criteria provided, single submitter clinical testing This variant is not reported in HGMD 2023.2, gnomAD (v2.1.1), dbSNP (v155) or LOVD (we submitted there) so far. The nucleotide position is moderat and aminoacid position is highly conservered, prediction (SIFT, PolyPhen-2, MutationTaster2021, AGVGD and REVEL) support a deleterious effect on the gene. In summary, the variant meets our criteria to be classified as likely pathogenic. ACMG: PM2, PP2, PP3str
Labcorp Genetics (formerly Invitae), Labcorp RCV003779274 SCV004649154 likely pathogenic not provided 2022-12-14 criteria provided, single submitter clinical testing 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). 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 COL4A1 protein function. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 359 of the COL4A1 protein (p.Gly359Val).

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