ClinVar Miner

Submissions for variant NM_002471.4(MYH6):c.4307G>A (p.Arg1436His)

gnomAD frequency: 0.00001  dbSNP: rs142556730
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000154758 SCV000204438 uncertain significance not specified 2015-04-04 criteria provided, single submitter clinical testing The p.Arg1436His variant in MYH6 has been previously identified by our laborator y in 1 Caucasian adult with HCM, who carried a pathogenic MYBPC3 variant suffici ent to explain disease. It has been identified in several populations (1/66760 E uropean, 2/8651 East Asian, and 1/11576 Latino chromosomes) by the Exome Aggrega tion Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs142556730). Compu tational prediction tools and conservation analysis suggest that this variant ma y impact the protein, though this information is not predictive enough to determ ine pathogenicity. In summary, the clinical significance of the p.Arg1436His var iant is uncertain.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000154758 SCV000919829 uncertain significance not specified 2018-08-13 criteria provided, single submitter clinical testing Variant summary: MYH6 c.4307G>A (p.Arg1436His) results in a non-conservative amino acid change located in the Myosin tail (IPR002928) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.8e-05 in 277188 control chromosomes (gnomAD). The observed variant frequency is approximately 2.3-fold above the estimated maximal expected allele frequency for a pathogenic variant in MYH6 causing Cardiomyopathy phenotype (2.5e-05), suggesting that the variant may be benign. However, this data must be interpreted cautiously due to the potential presence of individuals with cardiac phenotypes in gnomAD. To our knowledge, no occurrence of c.4307G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Labcorp Genetics (formerly Invitae), Labcorp RCV001205885 SCV001377165 uncertain significance Hypertrophic cardiomyopathy 14 2025-01-12 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1436 of the MYH6 protein (p.Arg1436His). This variant is present in population databases (rs142556730, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MYH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 178068). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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 RCV002326881 SCV002632917 uncertain significance Cardiovascular phenotype 2024-09-13 criteria provided, single submitter clinical testing The p.R1436H variant (also known as c.4307G>A), located in coding exon 28 of the MYH6 gene, results from a G to A substitution at nucleotide position 4307. The arginine at codon 1436 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002483342 SCV002779982 uncertain significance Hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1EE; Hypertrophic cardiomyopathy 14; Atrial septal defect 3; Sick sinus syndrome 3, susceptibility to 2021-07-26 criteria provided, single submitter clinical testing

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