ClinVar Miner

Submissions for variant NM_053025.4(MYLK):c.3824G>A (p.Arg1275Gln) (rs564792567)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000466129 SCV000550021 uncertain significance Aortic aneurysm, familial thoracic 7 2016-08-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1275 of the MYLK protein (p.Arg1275Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs564792567, ExAC 0.01%) but has not been reported in the literature in individuals with a MYLK-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: "Benign"; Align-GVGD: "Class C35"). 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 RCV000523772 SCV000621414 uncertain significance not provided 2017-10-05 criteria provided, single submitter clinical testing The R1275Q variant of uncertain significance in the MYLK gene has not been published as pathogenic or been reported as benign to our knowledge. R1275Q is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R1275Q 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 across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, no pathogenic missense variants in nearby residues have been reported in the Human Gene Mutation Database (Stenson et al., 2014).

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