Submissions for variant NM_002471.4(MYH6):c.831G>T (p.Gln277His)

gnomAD frequency: 0.00029  dbSNP: rs140660481

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172034	SCV000050999	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154662	SCV000204339	likely benign	not specified	2019-11-13	criteria provided, single submitter	clinical testing	The p.Gln277His variant in MYH6 is classified as likely benign because it has been identified in 0.14% (50/35424) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BS1
Labcorp Genetics (formerly Invitae), Labcorp	RCV001083211	SCV000557874	likely benign	Hypertrophic cardiomyopathy 14	2024-01-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000172034	SCV000565717	likely benign	not provided	2019-07-22	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23861362, 27789736, 29332214, 32880476)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769431	SCV000900824	benign	Cardiomyopathy	2021-08-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154662	SCV000917835	likely benign	not specified	2020-11-17	criteria provided, single submitter	clinical testing	Variant summary: MYH6 c.831G>T (p.Gln277His) results in a non-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 0.0004 in 251478 control chromosomes, predominantly at a frequency of 0.0014 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 56 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 Latino origin. c.831G>T has been reported in the literature in individuals affected with Cardiomyopathy and Hypoplastic left heart syndrome (Ng_2013, Tomita-Mitchell_2016, Pulignani_2018, Westphal_2019, Martinez-Matilla_2019). These reports 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. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (3x) and likely benign (3x). Based on the evidence outlined above, the variant was classified as likely benign.
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000999591	SCV001156293	likely benign	Brugada syndrome; Hypertrophic cardiomyopathy; Left ventricular noncompaction cardiomyopathy	2018-06-05	criteria provided, single submitter	research	MYH6 Gln277His has been identified in 2 HCM, 1 LVNC and 1 Brugada syndrome proband from our research program. This variant has been found in the Genome Aggregation Database (http://gnomad.broadinstitute.org/)at an allele frequency of 0.00037, which is higher then expected for any these inherited heart condition. Considering the variable phenotypes and population frequency we classify this variant as 'likely benign'.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV001256735	SCV001433141	uncertain significance	Hypertrophic cardiomyopathy 1	2019-12-10	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000172034	SCV001471549	uncertain significance	not provided	2019-07-26	criteria provided, single submitter	clinical testing	The MYH6 c.831G>T; p.Gln277His variant (rs140660481) is reported in the literature in individuals affected with congenital heart defects but not in individuals with dilated cardiomyopathy (Tomita-Mitchell 2016 and Pulignani 2018). However, this variant is also found in the Latino population with an allele frequency of 0.14 % (50 / 35,424 alleles) in the Genome Aggregation Database. This variant is reported as likely benign and VUS in ClinVar (Variation ID: 177985). The glutamine at codon 277 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict conflicting effects of this variant on protein structure/function. However, given the lack of clinical data in syndromes typically associated with MYH6 variants and functional data, the significance of the p.Gln277His variant is uncertain at this time.
Ambry Genetics	RCV002408687	SCV002675306	likely benign	Cardiovascular phenotype	2019-07-29	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.
Revvity Omics, Revvity	RCV000172034	SCV003815382	uncertain significance	not provided	2019-03-19	criteria provided, single submitter	clinical testing
Dept of Medical Biology, Uskudar University	RCV003318356	SCV004022054	uncertain significance	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: BS1, PP3
Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics	RCV004765314	SCV005374731	uncertain significance	Hypertrophic cardiomyopathy		no assertion criteria provided	research