ClinVar Miner

Submissions for variant NM_002471.3(MYH6):c.4016G>A (p.Arg1339Gln) (rs766238876)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000227324 SCV000287420 uncertain significance Familial hypertrophic cardiomyopathy 14 2018-09-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1339 of the MYH6 protein (p.Arg1339Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs766238876, ExAC 0.006%). This variant has not been reported in the literature in individuals with MYH6-related disease. ClinVar contains an entry for this variant (Variation ID: 239172). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). 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.
Ambry Genetics RCV000619363 SCV000736165 uncertain significance Cardiovascular phenotype 2017-12-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign)
GeneDx RCV000658372 SCV000780144 uncertain significance not provided 2018-05-24 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYH6 gene. The R1339Q variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 14/275374 (0.0051%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). Nevertheless, the R1339Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.

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