Submissions for variant NM_002471.4(MYH6):c.1763A>C (p.Asp588Ala)

gnomAD frequency: 0.00153  dbSNP: rs142992009

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172566	SCV000051407	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151221	SCV000199079	uncertain significance	not specified	2013-08-02	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Asp588Ala varia nt in MYH6 is present in 0.2% (19/8600) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs142992 009). It has also been reported in 1 individual with CHD (Granados-Riveron 2010) . Computational analyses (biochemical amino acid properties, conservation, Align GVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impac t to the protein. The variant?s population frequency suggests that it is more li kely benign but is too low to confidently rule out a disease-causing role. Addit ional information is needed to fully assess its clinical significance.
Eurofins Ntd Llc (ga)	RCV000151221	SCV000226269	likely benign	not specified	2015-06-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000989183	SCV000287397	likely benign	Hypertrophic cardiomyopathy 14	2024-01-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000172566	SCV000513788	likely benign	not provided	2021-04-14	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22955375, 8282798, 26085007, 20656787, 23396983, 28074886, 27789736, 23861362, 27760138, 27607113, 26284702, 21378987, 22194935, 19864899, 19808347, 15998695, 14573521, 8878443, 2969919)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000151221	SCV000697923	likely benign	not specified	2020-11-24	criteria provided, single submitter	clinical testing	Variant summary: MYH6 c.1763A>C (p.Asp588Ala) results in a non-conservative amino acid change located in the Myosin head, motor domain (IPR001609) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0018 in 252206 control chromosomes, predominantly at a frequency of 0.0032 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 128 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 Non-Finnish European origin. c.1763A>C has been reported in the literature in individuals affected with Cardiomyopathy (Theis_2015, Lopes_2015, Christiansen_2016, Neubauer_2017, Mates_2018, Jaaskelainen_2019). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submitters (evaluation after 2014) cite the variant as benign (1x), likely benign (6x) and uncertain significance (1x). Based on the evidence outlined above, the variant was classified as likely benign.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000151221	SCV000740615	likely benign	not specified	2016-09-08	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000172566	SCV000884187	likely benign	not provided	2020-08-17	criteria provided, single submitter	clinical testing
Mendelics	RCV000989183	SCV001139405	benign	Hypertrophic cardiomyopathy 14	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000172566	SCV001149146	benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	MYH6: BS1, BS2
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798462	SCV002043176	benign	Cardiomyopathy	2019-05-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002408642	SCV002716770	likely benign	Cardiovascular phenotype	2019-03-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Blueprint Genetics	RCV000143919	SCV000188793	benign	Primary familial hypertrophic cardiomyopathy	2014-12-05	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000172566	SCV001744409	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000151221	SCV001920957	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000172566	SCV001930035	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000151221	SCV001953424	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000172566	SCV001971278	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532623	SCV004720370	likely benign	MYH6-related disorder	2020-10-26	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).