ClinVar Miner

Submissions for variant NM_002474.3(MYH11):c.4993C>T (p.Arg1665Cys) (rs768569707)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000475772 SCV000543730 uncertain significance Aortic aneurysm, familial thoracic 4 2016-08-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1672 of the MYH11 protein (p.Arg1672Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs768569707, ExAC 0.01%) but has not been reported in the literature in individuals with a MYH11-related disease. 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. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000523310 SCV000620194 uncertain significance not provided 2017-08-23 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYH11 gene. The R1665C variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 1/8654 (0.012%) alleles from individuals of East Asian ancestry, and in 6/66740 (0.009%) alleles from individuals of Non-Finnish European ancestry in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R1665C 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. Additionally, this substitution occurs at a position where only amino acids with similar properties to arginine (R) are tolerated across species. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, this variant has not been observed in a significant number of affected individuals, and it lacks both segregation and functional studies which would further clarify its pathogenicity.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769659 SCV000901067 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2017-05-29 criteria provided, single submitter clinical testing
Color RCV000769659 SCV001340900 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2018-11-13 criteria provided, single submitter clinical testing

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