ClinVar Miner

Submissions for variant NM_000093.4(COL5A1):c.3203T>G (p.Val1068Gly) (rs372109796)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766817 SCV000249813 uncertain significance not provided 2015-03-02 criteria provided, single submitter clinical testing p.Val1068Gly (GTG>GGG): c.3203 T>G in exon 40 of the COL5A1 gene (NM_000093.3)A variant of unknown significance has been identified in the COL5A1 gene. The V1068G variant has not been published as a mutation or as a benign polymorphism to our knowledge. The V1068G variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Furthermore, a missense mutation in a nearby residue (G1072E) has been reported in association with EDS, however, the V1068G variant does not affect a Glycine residue in a Gly-X-Y motif in the triple helical region of the COL5A1 gene, where the majority of missense mutations occur (Symoens et al., 2012). Additionally, the V1068G variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved across species. Lastly, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This variant was found in COL5A1,TAADV2-1,TAAD
Invitae RCV000559236 SCV000631486 uncertain significance Ehlers-Danlos syndrome, classic type 2018-12-07 criteria provided, single submitter clinical testing This sequence change replaces valine with glycine at codon 1068 of the COL5A1 protein (p.Val1068Gly). The valine residue is moderately conserved and there is a moderate physicochemical difference between valine and glycine. This variant is present in population databases (rs372109796, ExAC 0.008%) but has not been reported in the literature in individuals with a COL5A1-related disease. ClinVar contains an entry for this variant (Variation ID: 212956). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. 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.
PreventionGenetics RCV000196527 SCV000302190 likely benign not specified criteria provided, single submitter clinical testing

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