ClinVar Miner

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

gnomAD frequency: 0.00029  dbSNP: rs140660481
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Total submissions: 12
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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 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
Invitae 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: 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 Omics 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

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