ClinVar Miner

Submissions for variant NM_000090.3(COL3A1):c.178G>A (p.Val60Ile) (rs762028131)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000468050 SCV000541794 uncertain significance Ehlers-Danlos syndrome, type 4 2016-11-30 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 60 of the COL3A1 protein (p.Val60Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs762028131, ExAC 0.01%) but has not been reported in the literature in individuals with a COL3A1-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 RCV000481681 SCV000573640 uncertain significance not provided 2017-02-24 criteria provided, single submitter clinical testing The V60I variant has not been publishedas pathogenic or been reported as benign to our knowledge. It is not observed at a significant frequency in largepopulation cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In addition,this substitution occurs at a position that is largely conserved across species. Nonetheless, the V60I variant is aconservative amino acid substitution, which is not likely to impact secondary protein structure as these residues sharesimilar properties. Moreover, the V60I variant does not affect a Glycine residue in a Gly-X-Y motif in the triplehelical region of the COL3A1 gene, where the majority of pathogenic missense variants occur (Stenson et al., 2014;Symoens et al., 2012). Finally, in silico analysis is inconsistent in its predictions as to whether or not the variant isdamaging to the protein structure/function.
Integrated Genetics/Laboratory Corporation of America RCV000780191 SCV000917250 uncertain significance not specified 2018-06-20 criteria provided, single submitter clinical testing Variant summary: COL3A1 c.178G>A (p.Val60Ile) results in a conservative amino acid change located in the vWFC domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.3e-05 in 245564 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.178G>A in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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