ClinVar Miner

Submissions for variant NM_053025.4(MYLK):c.2663G>A (p.Arg888His) (rs528507616)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480103 SCV000573545 uncertain significance not provided 2018-01-23 criteria provided, single submitter clinical testing The R888H variant has not been publishedas pathogenic or been reported as benign to our knowledge. It is not observed at a significant frequency in largepopulation cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R888Hsubstitution occurs at a position where only amino acids with similar properties to arginine (R) are tolerated acrossspecies. However, R888H is a conservative amino acid substitution, which is not likely to impact secondary proteinstructure as these residues share similar properties. Finally, in silico analysis is inconsistent in its predictions as towhether or not the variant is damaging to the protein structure/function.
Invitae RCV000690992 SCV000818727 uncertain significance Aortic aneurysm, familial thoracic 7 2018-06-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 888 of the MYLK protein (p.Arg888His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs528507616, ExAC 0.02%). This variant has not been reported in the literature in individuals with MYLK-related disease. ClinVar contains an entry for this variant (Variation ID: 423801). 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 C25"). 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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