ClinVar Miner

Submissions for variant NM_000090.4(COL3A1):c.3536G>T (p.Gly1179Val)

dbSNP: rs587779627
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV002509211 SCV002819097 likely pathogenic not provided 2022-07-01 criteria provided, single submitter clinical testing 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); 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: 24922459, 9036918, 10706896)
Labcorp Genetics (formerly Invitae), Labcorp RCV000087590 SCV003525178 likely pathogenic Ehlers-Danlos syndrome, type 4 2022-03-11 criteria provided, single submitter clinical testing 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. 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). 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: 101352). This missense change has been observed in individual(s) with vascular 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 1179 of the COL3A1 protein (p.Gly1179Val).
Collagen Diagnostic Laboratory, University of Washington RCV000087590 SCV000120480 pathogenic Ehlers-Danlos syndrome, type 4 no assertion criteria provided clinical testing

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