ClinVar Miner

Submissions for variant NM_000393.5(COL5A2):c.4358G>A (p.Arg1453Gln) (rs149064715)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000195660 SCV000249993 uncertain significance not specified 2016-08-29 criteria provided, single submitter clinical testing The R1453Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R1453Q 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. The R1453Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Finally, the R1453Q variant 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).Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000461727 SCV000547876 uncertain significance Ehlers-Danlos syndrome, classic type 2018-07-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1453 of the COL5A2 protein (p.Arg1453Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs149064715, ExAC 0.04%) but has not been reported in the literature in individuals with a COL5A2-related disease. ClinVar contains an entry for this variant (Variation ID: 213130). 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: "Unknown"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change that is not predicted to affect protein function or cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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