ClinVar Miner

Submissions for variant NM_000090.3(COL3A1):c.1763G>A (p.Gly588Asp) (rs587779691)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000621506 SCV000738526 pathogenic Cardiovascular phenotype 2016-06-03 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s);Structural Evidence
Invitae RCV000087689 SCV000831467 pathogenic Ehlers-Danlos syndrome, type 4 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 588 of the COL3A1 protein (p.Gly588Asp). 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 individuals affected with Ehlers Danlos syndrome type IV (PMID: 10706896, 24922459). ClinVar contains an entry for this variant (Variation ID: 101451). 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, missense variants at 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000087689 SCV000967697 likely pathogenic Ehlers-Danlos syndrome, type 4 2019-03-01 criteria provided, single submitter clinical testing The p.Gly588Asp variant in COL3A1 has been reported in 2 individuals with clinic al features of Ehlers-Danlos syndrome type IV (EDS IV; Pepin 2000, Pepin 2014). This variant was absent from large population studies and has been reported as p athogenic in ClinVar (Variation ID 101451). Computational prediction tools and c onservation analysis suggest that the p.Gly588Asp variant may impact the protein . Variants in COL3A1 affecting conserved glycine (Gly) residues of the G-X-Y rep eat region in the triple helical collagen domain, where this variant is located, are strongly associated with EDS IV (Pepin 2000, Pepin 2014, Frank 2015). Furth ermore, a different missense variant affecting the same position, p.Gly588Val, h as been reported in an individual with EDS IV (Frank 2015). In summary, although additional studies are required to fully establish its clinical significance, t his variant meets criteria to be classified as likely pathogenic for autosomal d ominant EDS IV. ACMG/AMP Criteria applied: PM1, PM2, PM5, PP3, PS4_Supporting.
Collagen Diagnostic Laboratory,University of Washington RCV000087689 SCV000120581 pathogenic Ehlers-Danlos syndrome, type 4 no assertion criteria provided clinical testing

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