ClinVar Miner

Submissions for variant NM_000090.3(COL3A1):c.1330G>A (p.Gly444Arg) (rs587779489)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Collagen Diagnostic Laboratory,University of Washington RCV000087422 SCV000120306 pathogenic Ehlers-Danlos syndrome, type 4 no assertion criteria provided clinical testing
GeneDx RCV000494523 SCV000582884 likely pathogenic not provided 2016-02-10 criteria provided, single submitter clinical testing The G444R variant has been previously published in association with EDS type IV (Shimaoka et al., 2010; Pepin et al., 2014). Shimaoka et al. (2010) identified G444R in a 30 year old Japanese man with a clinical history of extensive bruising, characteristic facial appearance, hypermobility of small joints, arterial aneurysm/dissection/rupture, and a family history consistent with EDS type IV. G444R was also reported in association with EDS type IV in six probands; however, no specific clinical information or segregation analyses were provided (Pepin et al., 2014). The G444R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G444R 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. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, the G444R variant affects a Glycine residue in a Gly-X-Y motif in the triple helical region of the COL3A1 gene, where the majority of pathogenic missense variants occur (Stenson et al., 2014; Symoens et al., 2012).Therefore, this variant is likely pathogenic
Invitae RCV000087422 SCV000815742 pathogenic Ehlers-Danlos syndrome, type 4 2018-11-29 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 444 of the COL3A1 protein (p.Gly444Arg). 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 observed in several individuals affected with vascular Ehlers-Danlos syndrome (PMID: 10706896, 20518783, 22492385). This variant is also known as G277R in the literature. ClinVar contains an entry for this variant (Variation ID: 101185). 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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