ClinVar Miner

Submissions for variant NM_004370.6(COL12A1):c.7477G>A (p.Glu2493Lys) (rs372985511)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000444377 SCV000536557 uncertain significance not provided 2017-02-07 criteria provided, single submitter clinical testing The E2493K variant in the COL12A1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The E2493K variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E2493K 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 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. We interpret E2493K as a variant of uncertain significance.
Invitae RCV000652906 SCV000774778 uncertain significance Ullrich congenital muscular dystrophy 2; Bethlem myopathy 2 2018-11-27 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 2493 of the COL12A1 protein (p.Glu2493Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs372985511, ExAC 0.006%). This variant has not been reported in the literature in individuals with COL12A1-related disease. ClinVar contains an entry for this variant (Variation ID: 393184). 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: "Possibly Damaging"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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