Submissions for variant NM_002471.4(MYH6):c.4906C>T (p.Arg1636Cys)

gnomAD frequency: 0.00116  dbSNP: rs149460065

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037520	SCV000061178	likely benign	not specified	2013-03-06	criteria provided, single submitter	clinical testing	Arg1636Cys in exon 33 of MYH6: This variant is not expected to have clinical sig nificance because it has been identified in 0.4% (18/4406) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS/; dbSNP rs149460065). Arg1636Cys in exon 33 of MYH6 (rs149460065; allele frequency = 0.4%, 18/4406) **
Invitae	RCV000226808	SCV000287434	likely benign	Hypertrophic cardiomyopathy 14	2024-01-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000241881	SCV000318946	benign	Cardiovascular phenotype	2018-11-30	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV001719744	SCV000715377	likely benign	not provided	2020-05-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037520	SCV001362622	likely benign	not specified	2019-11-11	criteria provided, single submitter	clinical testing	Variant summary: MYH6 c.4906C>T (p.Arg1636Cys) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Five 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 282768 control chromosomes, predominantly at a frequency of 0.004 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 160 fold 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 African or African-American origin. c.4906C>T has been reported in the literature in an individual affected with sudden cardiac death (Seidelmann_2017). This report however, does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=2) and uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Clinical Genetics, Academic Medical Center	RCV000037520	SCV001925031	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000037520	SCV001927135	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000037520	SCV001976028	benign	not specified		no assertion criteria provided	clinical testing