ClinVar Miner

Submissions for variant NM_000393.5(COL5A2):c.3488A>G (p.Gln1163Arg) (rs758412337)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000469203 SCV000547868 uncertain significance Ehlers-Danlos syndrome, classic type 2016-06-24 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 1163 of the COL5A2 protein (p.Gln1163Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is present in population databases (rs758412337, ExAC 0.07%) but has not been reported in the literature in individuals with a COL5A2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000498779 SCV000590266 uncertain significance not provided 2017-06-02 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the COL5A2 gene. Although the Q1163R variant has not been published as pathogenic or been reported as benign to our knowledge, it is classified as a variant of uncertain significance in ClinVar by a different clinical laboratory in association with classical Ehlers-Danlos syndrome (cEDS, EDS I and II) (ClinVar SCV000547868.1; Landrum et al., 2016). The Q1163R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Additionally, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, this variant has been observed in 7/9524 (0.07%) alleles from individuals of Latino ancestry in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Furthermore, Q1163R does not affect a Glycine residue in a Gly-X-Y motif in the triple helical region of the COL5A2 gene, where the majority of pathogenic missense variants occur (Stenson et al., 2014; Symoens et al., 2012). However, in contrast to several other collagen genes, relatively few pathogenic Glycine substitutions have been reported in COL5A2 in association with Ehlers-Danlos syndrome. Most pathogenic variants in COL5A2 are in-frame splice site changes that cause exon skipping (Symoens et al., 2012).
Ambry Genetics RCV000618510 SCV000738742 uncertain significance Cardiovascular phenotype 2017-07-11 criteria provided, single submitter clinical testing Insufficient evidence

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