ClinVar Miner

Submissions for variant NM_001845.6(COL4A1):c.3743G>A (p.Gly1248Glu)

dbSNP: rs2139154591
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002012358 SCV002285757 likely pathogenic not provided 2021-09-20 criteria provided, single submitter clinical testing Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This sequence change replaces glycine with glutamic acid at codon 1248 of the COL4A1 protein (p.Gly1248Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with COL4A1-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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). 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.
Molecular Genetics, Royal Melbourne Hospital RCV003994375 SCV004812598 likely pathogenic Brain small vessel disease 1 with or without ocular anomalies 2023-07-07 criteria provided, single submitter clinical testing This sequence change in COL4A1 is predicted to replace glycine with glutamic acid at codon 1248, p.(Gly1248Glu). The glycine residue is highly conserved (86/87 vertebrates, UCSC), and alters a critical glycine residue in a collagen triple helix repeat (Gly-X-Y) in the collagenous domain (PMID: 8218237). There is a moderate physicochemical difference between glycine and glutamic acid. This variant is absent from the population database gnomAD v2.1 and v3.1. This variant has been identified as a de novo occurrence with unconfirmed parental relationships in an individual with a phenotype consistent with COL4A1-related disorders (Royal Melbourne Hospital). Computational evidence predicts a deleterious effect for the missense substitution (REVEL=0.994). Based on the classification scheme RMH Modified ACMG Guidelines v1.6.1, this variant is classified as a LIKELY PATHOGENIC. Following criteria are met: PM1, PP3_Moderate, PM2_Supporting, PM6_Supporting.

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