ClinVar Miner

Submissions for variant NM_001845.6(COL4A1):c.2008G>A (p.Gly670Arg)

dbSNP: rs1878248687
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV001090430 SCV001245974 pathogenic not provided 2019-11-01 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV001090430 SCV002064354 likely pathogenic not provided 2018-07-09 criteria provided, single submitter clinical testing DNA sequence analysis of the COL4A1 gene demonstrated a sequence change, c.2008G>A, in exon 28 that results in an amino acid change, p.Gly670Arg. The p.Gly670Arg change affects a highly conserved amino acid residue located in the triple helix repeat domain of the COL4A1 protein that is known to be functional. This variant is absent from population databases (ExAC, GnomAD). The p.Gly670Arg substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL).This particular amino acid change has been described in the literature in the de novo state in a patient with features of COL4A1 disorders including seizures and porencephaly (Meuwissen et. al., 2015). Variants affecting the glycine residues at the triple helical domain of the COL4A1 protein are predicted to affect protein stability and exert a dominant negative effect (Meuwissen et. al., 2015). Several variants affecting other glycine residues in this domain have been reported in the literature in COL4A1-related disorders (Plaisier et. al., GeneReviews, 2016). These collective evidences indicate that this sequence change is the likely cause of this phenotype, however functional studies have not been performed to prove this conclusively.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002271619 SCV002555735 likely pathogenic Brain small vessel disease 1 with or without ocular anomalies 2022-06-01 criteria provided, single submitter clinical testing Variant summary: COL4A1 c.2008G>A (p.Gly670Arg) results in a non-conservative amino acid change located in the Collagen triple helix repeat (IPR008160, Gly-Xaa-Yaa) of the encoded protein sequence. Glycine residues play an important role for the stabilization of collagenous triple helical domain and most of the pathogenic variants reported in COL4A1-related disorders affect highly conserved glycine residues within the collagenous domain of the protein (GeneReviews). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246426 control chromosomes (gnomAD). c.2008G>A has been reported in the literature in at-least two individuals affected with Porencephaly. One infant with this variant presented seizures caused by intracerebral hemorrhages and one terminated fetus (at 35 weeks) presented hemorrhagic supratentorial lesions (examples: Maurice_2021 and Meuwissen_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=1) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV003763804 SCV002568193 pathogenic COL4A1-related disorder 2022-06-08 criteria provided, single submitter clinical testing PS2_Very Strong, PS4_Moderate, PM1, PM2, PP2, PP3
Invitae RCV001090430 SCV004296536 pathogenic not provided 2024-01-20 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 670 of the COL4A1 protein (p.Gly670Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with COL4A1-related conditions (PMID: 25719457, 32515830). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 870803). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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). For these reasons, this variant has been classified as Pathogenic.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV001090430 SCV001955791 likely pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV001090430 SCV001971887 pathogenic not provided no assertion criteria provided clinical testing

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