ClinVar Miner

Submissions for variant NM_001845.6(COL4A1):c.2788G>A (p.Gly930Ser)

dbSNP: rs2139163058
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centogene AG - the Rare Disease Company RCV002246527 SCV002059467 likely pathogenic Brain small vessel disease 1 with or without ocular anomalies 2020-05-18 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002542440 SCV003316882 pathogenic not provided 2024-04-22 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 930 of the COL4A1 protein (p.Gly930Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of porencephaly, hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (PMID: 33298904). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 1333877). 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.
Baylor Genetics RCV002246527 SCV003836180 likely pathogenic Brain small vessel disease 1 with or without ocular anomalies 2022-01-28 criteria provided, single submitter clinical testing
GeneDx RCV002542440 SCV004022956 pathogenic not provided 2023-07-26 criteria provided, single submitter clinical testing Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A1 gene, where the majority of pathogenic missense variants occur, and is predicted to disrupt normal protein folding and function (HGMD; Weng et al., 2012; Yoneda et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33298904, 22522439, 23225343)

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