Submissions for variant NM_000257.4(MYH7):c.77C>T (p.Ala26Val)

gnomAD frequency: 0.00021  dbSNP: rs186964570

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000758056	SCV000564467	benign	Cardiomyopathy	2016-12-15	reviewed by expert panel	curation	The filtering allele frequency of the c.77C>T (p.Ala26Val) variant in the MYH7 gene is 0.55% (60/8646) of East Asian chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372).
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000148713	SCV000050867	benign	Primary familial hypertrophic cardiomyopathy	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036003	SCV000059655	likely benign	not specified	2012-12-12	criteria provided, single submitter	clinical testing	Ala26Val in exon 3 of MYH7: This variant has been reported in 10 HCM probands of Asian descent and was absent from 832 race-matched control chromosomes (Konno 2 005, Liu 2005, Song 2005, Wang 2009). However, one of the probands had another p athogenic HCM variant on the same copy of the gene which segregated with all 8 a ffected family members (Wang 2009). Although segregation in 3 family members was observed in one other family, an additional 5 individuals had the variant witho ut disease including three over age 70 (Liu 2005). Our laboratory has observed t his variant in one HCM proband and one DCM proband, neither with a family histor y of disease, out of over 3500 cases tested (1/215 Asian probands). This variant has been observed in 1.5% (6/388) of Chinese chromosomes in a broad population (1000 Genomes project, rs186964570), suggesting that it is not disease causing i n isolation. Computational analyses (biochemical amino acid properties, conserva tion, AlignGVGD, PolyPhen2, and SIFT) suggest that the Ala26Val variant is less likely to impact the protein, particularly given the lack of evolutionary conser vation in some mammalian species. In summary, the high frequency of this variant in Asians and poor evolutionary conservation suggest that this variant is benig n but additional data is needed to establish this with certainty. A modifying e ffect cannot be ruled out.
GeneDx	RCV000036003	SCV000208658	likely benign	not specified	2015-08-11	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000168831	SCV000267409	uncertain significance	Hypertrophic cardiomyopathy 1	2016-03-18	criteria provided, single submitter	reference population
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000168831	SCV000296899	uncertain significance	Hypertrophic cardiomyopathy 1	2015-10-12	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV003320037	SCV000386354	likely benign	Myosin storage myopathy	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000319538	SCV000386355	likely benign	Dilated cardiomyopathy 1S	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000374158	SCV000386356	likely benign	MYH7-related skeletal myopathy	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000168831	SCV000386357	likely benign	Hypertrophic cardiomyopathy 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000334846	SCV000386358	likely benign	Left ventricular noncompaction cardiomyopathy	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV000279740	SCV000557966	benign	Hypertrophic cardiomyopathy	2024-01-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000618296	SCV000740061	likely benign	Cardiovascular phenotype	2016-10-27	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.
Color Diagnostics, LLC DBA Color Health	RCV000758056	SCV000903190	benign	Cardiomyopathy	2018-07-09	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000721101	SCV001144680	benign	not provided	2019-06-30	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000721101	SCV001433100	likely pathogenic	not provided	2018-09-24	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490429	SCV002799469	likely benign	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2022-05-24	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148713	SCV000190443	uncertain significance	Primary familial hypertrophic cardiomyopathy	2014-06-01	no assertion criteria provided	research
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000721101	SCV000280379	likely benign	not provided	2016-08-22	no assertion criteria provided	provider interpretation	Given the allele frequency in East Asians in ExAC, we consider this variant likely benign (AF 0.0069).