Submissions for variant NM_000257.4(MYH7):c.4909G>A (p.Ala1637Thr)

gnomAD frequency: 0.00034  dbSNP: rs141122361

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000758026	SCV000564454	likely benign	Cardiomyopathy	2021-03-22	reviewed by expert panel	curation	The c.4909G>A (p.Ala1637Thr) variant in MYH7 has been observed in 0.060% (FAF 95% CI; 22/24960) of African chromosomes in gnomAD v2.1.1 (http://gnomad.broadinstitute.org), which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BS1; Kelly 2018 PMID:29300372). Additionally, computational prediction tools and conservation analysis suggest that this variant may not impact the protein (BP4). In summary, this variant meets criteria to be classified as likely benign for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): BS1, BP4
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035938	SCV000059589	likely benign	not specified	2018-07-19	criteria provided, single submitter	clinical testing	Ala1637Thr in exon34 of MYH7: This variant is not expected to have clinical sign ificance due to a lack of evolutionary conservation of the affected amino acid ( of note, 5 mammalian species have a threonine (Thr) at this position despite hig h nearby amino acid conservation). In addition, this variant was predicted to be benign using a computational tool clinically validated by our laboratory. This tool's benign prediction is estimated to be correct 89% of the time (Jordan 2011 ). It has also been identified in 5/10402 African American chromosomes by the Ex ome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs14112 2361).
CSER _CC_NCGL, University of Washington	RCV000148696	SCV000190425	uncertain significance	Primary familial hypertrophic cardiomyopathy	2014-06-01	criteria provided, single submitter	research	Allele frequency may indicate a low penetrance or likely benign variant
GeneDx	RCV001703873	SCV000208612	likely benign	not provided	2020-03-09	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24055113, 20800588, 20624503, 23299917, 25637381, 24510615, 22958901, 23782526, 23403236, 29300372)
Invitae	RCV000465008	SCV000546282	uncertain significance	Hypertrophic cardiomyopathy	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1637 of the MYH7 protein (p.Ala1637Thr). This variant is present in population databases (rs141122361, gnomAD 0.09%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 20624503, 23782526, 27574918). ClinVar contains an entry for this variant (Variation ID: 43044). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000620929	SCV000735725	likely benign	Cardiovascular phenotype	2020-07-20	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.
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000853439	SCV000996350	likely benign	Ventricular fibrillation	2017-11-21	criteria provided, single submitter	research	The MYH7 Ala1637Thr variant has been previously reported in a HCM patient (Millat G et al., 2010), but has also been identified in a healthy control (Kapplinger JD, et al., 2014). We identified this variant in a proband diagnosed with idiopathic ventricular fibrillation, who has a family history of sudden death. The variant is present in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) at an allele frequency >0.000075, which is higher then expected for an inherited arrhythmia syndrome. In silico tools SIFT, PolyPhen2 and Polyphen-HCM predict this variant to be benign, however MutationTaster predicts this variant to be disease-causing. In summary, the variant is unlikely to be causing disease as it is present in the general population at an elevated frequency, has been identified in atleast 1 control and 3/4 in silico tools predict the variant to be benign, therefore we classify MYH7 Ala1637Thr as "likely benign".
Mendelics	RCV000989185	SCV001139408	benign	Hypertrophic cardiomyopathy 1	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000758026	SCV001349565	uncertain significance	Cardiomyopathy	2023-02-21	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1637 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 20624503, 27574918). This variant has also been identified in 25/282810 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
New York Genome Center	RCV002227441	SCV002506913	uncertain significance	Dilated cardiomyopathy 1S	2021-04-30	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001703873	SCV003817731	uncertain significance	not provided	2023-03-16	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000758026	SCV003838744	likely benign	Cardiomyopathy	2021-10-19	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003952409	SCV004783522	likely benign	MYH7-related condition	2022-04-28	criteria provided, single submitter	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).