ClinVar Miner

Submissions for variant NM_000090.4(COL3A1):c.836G>A (p.Gly279Asp)

dbSNP: rs587779593
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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 RCV000087545 SCV001578723 pathogenic Ehlers-Danlos syndrome, type 4 2024-05-06 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 279 of the COL3A1 protein (p.Gly279Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with vascular Ehlers-Danlos syndrome (PMID: 22019127, 25758994, 30474650). ClinVar contains an entry for this variant (Variation ID: 101307). 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 COL3A1 protein function with a positive predictive value of 95%. This variant disrupts the triple helix domain of COL3A1. 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 COL3A1, variants that affect these glycine residues are significantly enriched in individuals with disease (PMID: 24922459, 25758994) compared to the general population (ExAC). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences RCV004528787 SCV004105050 pathogenic COL3A1-related disorder 2023-07-31 criteria provided, single submitter clinical testing The COL3A1 c.836G>A variant is predicted to result in the amino acid substitution p.Gly279Asp. This variant results in substitution of a glycine residue with another amino acid in the Gly-X-Y triple helical domain of COL3A1; such substitutions are known to be causative for vascular Ehlers-Danlos syndrome type IV (Pepin et al. 2014. PubMed ID: 24922459). The c.836G>A variant was reported in multiple individuals with vascular Ehlers-Danlos syndrome type IV (Drera et al. 2011. PubMed ID: 22019127; Legrand et al. 2018. PubMed ID: 30474650; Supplementary Table 4, Frank et al. 2015. PubMed ID: 25758994) and was confirmed to have arisen de novo in at least one patient (Legrand et al. 2018. PubMed ID: 30474650). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Collagen Diagnostic Laboratory, University of Washington RCV000087545 SCV000120432 pathogenic Ehlers-Danlos syndrome, type 4 no assertion criteria provided clinical testing

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