ClinVar Miner

Submissions for variant NM_000090.4(COL3A1):c.2870G>T (p.Gly957Val)

dbSNP: rs587779654
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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 RCV000087684 SCV000961962 pathogenic Ehlers-Danlos syndrome, type 4 2023-06-22 criteria provided, single submitter clinical testing 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. ClinVar contains an entry for this variant (Variation ID: 101446). This missense change has been observed in individual(s) with Ehlers-Danlos syndrome (PMID: 24922459; Invitae). 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 957 of the COL3A1 protein (p.Gly957Val). 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. This variant disrupts the p.Gly957 amino acid residue in COL3A1. Other variant(s) that disrupt this residue have been observed in individuals with COL3A1-related conditions (PMID: 2492273, 24650746), which suggests that this may be a clinically significant amino acid residue.
GeneDx RCV004589550 SCV005079349 pathogenic not provided 2023-06-13 criteria provided, single submitter clinical testing Has been reported in individuals with vascular Ehlers-Danlos syndrome (vEDS) (Pepin et al., 2014; Frank et al., 2015); 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; Occurs in the triple helical domain and replaces the glycine in the canonical Gly-X-Y repeat; missense substitution of a canonical glycine residue is expected to disrupt normal protein folding and function, and this is an established mechanism of disease (HGMD); This variant is associated with the following publications: (PMID: 25758994, 24922459)
Collagen Diagnostic Laboratory, University of Washington RCV000087684 SCV000120576 pathogenic Ehlers-Danlos syndrome, type 4 no assertion criteria provided clinical testing

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