Submissions for variant NM_002471.4(MYH6):c.2890G>T (p.Ala964Ser)

gnomAD frequency: 0.00148  dbSNP: rs144907522

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000037463	SCV000051406	benign	not specified	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037463	SCV000061121	likely benign	not specified	2015-11-09	criteria provided, single submitter	clinical testing	p.Ala964Ser in exon 22 of MYH6: This variant is not expected to have clinical si gnificance because it has been identified in 0.5% (51/10406) of African chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs144907522).
Invitae	RCV000461438	SCV000557925	benign	Hypertrophic cardiomyopathy 14	2024-01-12	criteria provided, single submitter	clinical testing
GeneDx	RCV001719743	SCV000715074	likely benign	not provided	2021-06-07	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27789736, 23861362)
Ambry Genetics	RCV000618195	SCV000736625	likely benign	Cardiovascular phenotype	2018-02-05	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037463	SCV000919832	likely benign	not specified	2018-11-05	criteria provided, single submitter	clinical testing	Variant summary: MYH6 c.2890G>T (p.Ala964Ser) results in a conservative amino acid change located in the Myosin tail domain 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 0.00048 in 277246 control chromosomes, predominantly at a frequency of 0.005 within the African subpopulation in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 200 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 African origin. c.2890G>T has been reported in the literature in individuals affected with hypoplastic left heart syndrome (Tomita-Mitchell_2016). These report(s) do 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. 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 benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001719743	SCV001470943	likely benign	not provided	2022-09-20	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477092	SCV002798655	likely benign	Hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1EE; Hypertrophic cardiomyopathy 14; Atrial septal defect 3; Sick sinus syndrome 3, susceptibility to	2022-04-22	criteria provided, single submitter	clinical testing