ClinVar Miner

Submissions for variant NM_002471.4(MYH6):c.4193G>A (p.Arg1398Gln) (rs150815925)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172024 SCV000054808 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000223030 SCV000272026 uncertain significance not specified 2015-07-01 criteria provided, single submitter clinical testing The p.Arg1398Gln variant in MYH6 has been previously reported in 1 adult with ca rdiac dysrhythmia and 1 unaffected adult with a family history of DCM through a whole exome sequencing study (Gonzalez-Garay 2013). It has also been identified in 36/66590 European chromosomes by the Exome Aggregation Consortium (ExAC, http ://; dbSNP rs150815925). Computational prediction tools a nd conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg1398Gln varian t is uncertain.
Ambry Genetics RCV000618730 SCV000737361 uncertain significance Cardiovascular phenotype 2018-10-03 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000647058 SCV000768845 uncertain significance Familial hypertrophic cardiomyopathy 14 2019-10-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1398 of the MYH6 protein (p.Arg1398Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs150815925, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in two individuals affected with hypertrophic cardiomyopathy and in one individual affected with dilated cardiomyopathy who also carried a pathogenic variant in the MYH7 gene (PMID: 24082139, 26383259, 26656175). ClinVar contains an entry for this variant (Variation ID: 191712). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000172024 SCV000884190 uncertain significance not provided 2018-05-27 criteria provided, single submitter clinical testing The p.Arg1398Gln variant (rs150815925) was reported in two patients, each with dilated and hypertrophic cardiomyopathy (Gonzalez-Garay 2013 and Bottillo 2016). This variant was also observed in one individual selected from a large cohort not selected for cardiomyopathy, and classified as uncertain based on population frequency (Ng 2013). This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.07 percent in the East Asian population (identified on 21 out of 30,782 chromosomes) and has been reported to the ClinVar database (Variation ID: 191712). The arginine at position 1398 is highly conserved up to Opossum considering 5 species and computational analyses of the effects of the p.Arg1398Gln variant on protein structure and function provides conflicting results (SIFT: damaging, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Arg1398Gln variant with certainty.
Integrated Genetics/Laboratory Corporation of America RCV000223030 SCV000917838 uncertain significance not specified 2018-09-11 criteria provided, single submitter clinical testing Variant summary: MYH6 c.4193G>A (p.Arg1398Gln) results in a conservative amino acid change located in the Myosin tail (IPR002928) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 277100 control chromosomes (gnomAD and publications). The observed variant frequency is approximately 15-fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH6 causing Cardiomyopathy phenotype (2.5e-05), suggesting that the variant is benign. The variant, c.4193G>A, has been reported in the literature in individuals affected with congenital heart disease and Cardiomyopathy (Bottillo_2015, Gonzalez-Garay_2013, Hertz_2016). Co-occurrences with other pathogenic variant(s) have been reported (MYH7 c.G428A, p.R143Q)(Bottillo_2015), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001171182 SCV001333874 likely benign Cardiomyopathy 2018-03-26 criteria provided, single submitter clinical testing

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