ClinVar Miner

Submissions for variant NM_002471.4(MYH6):c.1252G>A (p.Val418Met) (rs147606900)

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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 RCV000172033 SCV000054818 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037439 SCV000061097 uncertain significance not specified 2012-07-31 criteria provided, single submitter clinical testing The Val418Met variant in MYH6 has been identified in 1/8600 European American an d 1/4406 African American chromosomes from broad populations by the NHLBI Exome sequencing project (; dbSNP rs72646819). These c ould represent presymptomatic individuals. Computational analyses (biochemical a mino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provi de strong support for or against an impact to the protein. Additional informatio n is needed to fully assess the clinical significance of this variant.
Ambry Genetics RCV000254507 SCV000319710 likely benign Cardiovascular phenotype 2019-03-18 criteria provided, single submitter clinical testing Subpopulation frequency in support of benign classification
Invitae RCV001088230 SCV000648222 likely benign Familial hypertrophic cardiomyopathy 14 2019-12-31 criteria provided, single submitter clinical testing
GeneDx RCV000037439 SCV000721902 likely benign not specified 2018-01-08 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852697 SCV000995409 likely benign Cardiomyopathy 2018-02-11 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000037439 SCV001431930 likely benign not specified 2020-08-03 criteria provided, single submitter clinical testing Variant summary: MYH6 c.1252G>A (p.Val418Met) results in a conservative amino acid change located in the Myosin head, motor domain 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 0.00023 in 251484 control chromosomes, predominantly at a frequency of 0.002 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 80 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH6 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1252G>A has been reported in the literature in individuals affected with DCM and HCM (Pugh_2014, Mademont-Soler_2017, Tran_2019). These reports also suggest that this variant is unlikely to associate with Cardiomyopathy. 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 likely benign. Based on the evidence outlined above, the variant was classified as likely benign.

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