ClinVar Miner

Submissions for variant NM_000090.3(COL3A1):c.2168G>A (p.Gly723Asp) (rs587779581)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Collagen Diagnostic Laboratory,University of Washington RCV000087530 SCV000120417 pathogenic Ehlers-Danlos syndrome, type 4 no assertion criteria provided clinical testing
Invitae RCV000087530 SCV000283458 pathogenic Ehlers-Danlos syndrome, type 4 2016-03-08 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 723 of the COL3A1 protein (p.Gly723Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in an individual affected with Ehlers-Danlos syndrome (PMID: 24922459). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. Glycine residues within the triple helix region are crucial to maintain fibrillar collagens structure and stability (PMID: 7695699, 19344236). In the case of COL3A1, the majority of missense substitutions within the triplex helix domain affect glycine residues in patients with vascular Ehlers-Danlos syndrome (PMID: 24922459, 25758994). In summary, this variant is a rare missense change that is absent in the general population, it has been reported in two affected patients, and it affects one of the glycine residues within the triple helix of the COL3A1 protein, which is thought to be damaging. For these reasons, it has been classified as Pathogenic.

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