ClinVar Miner

Submissions for variant NM_000090.3(COL3A1):c.1618G>A (p.Gly540Arg) (rs587779584)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Collagen Diagnostic Laboratory,University of Washington RCV000087535 SCV000120422 pathogenic Ehlers-Danlos syndrome, type 4 no assertion criteria provided clinical testing
GeneDx RCV000181084 SCV000233360 pathogenic not provided 2018-02-19 criteria provided, single submitter clinical testing The G540R variant in the COL3A1 gene has been reported previously in multiple unrelated individual with Ehlers-Danlos syndrome, type IV (vascular type) (Pepin et al., 2014; Kerwin et al., 2008; Smith et al., 1997). The G540R variant is not observed in large population cohorts (Lek et al., 2016). The G540R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Other missense variants affecting the Gly-X-Y repeat of the triple helix domain (G549E, G552R) have been reported in the Human Gene Mutation Database in association with Ehlers-Danlos syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, based on the ACMG recommendations, G540R is interpreted as a known pathogenic sequence change.
Integrated Genetics/Laboratory Corporation of America RCV000087535 SCV000695357 pathogenic Ehlers-Danlos syndrome, type 4 2016-06-17 criteria provided, single submitter clinical testing Variant summary: The COL3A1 c.1618G>A (p.Gly540Arg) variant involves the alteration of a conserved critical nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. Other mutations affecting Glycine residues in the Gly-X-Y repeat of the triple helix domain (Gly519Glu, Gly549Glu, Gly567Glu) have been reported in association with EDS, further supporting the functional importance of this region of the protein. This variant is absent in 120568 control chromosomes and has been reported in multiple affected individuals with EDS type IV. In addition, multiple clinical diagnostic laboratories classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000087535 SCV000631629 pathogenic Ehlers-Danlos syndrome, type 4 2018-03-15 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 540 of the COL3A1 protein (p.Gly540Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in families and individuals affected with Ehlers–Danlos syndrome  (PMID: 10706896, 25355833, 24922459).  This variant is also known as p.Gly373Arg in the literature.  ClinVar contains an entry for this variant (Variation ID: 101297). 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.

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