Submissions for variant NM_000257.4(MYH7):c.3286G>T (p.Asp1096Tyr)

gnomAD frequency: 0.00013  dbSNP: rs45478699

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000758039	SCV000577981	likely benign	Cardiomyopathy	2021-03-22	reviewed by expert panel	curation	The c.3286G>T (p.Asp1096Tyr) variant in MYH7 has been identified in 0.023% (FAF 95% CI; 40/129162) of European chromosomes in gnomAD v2.1.1 (https://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). Allowing a variant to reach a likely benign classification based on BS1 alone represents a revision of the original ACMG/AMP framework by ClinGen’s Sequence Variant Interpretation Working Group (Tavtigian 2018 PMID: 29300386). Additionally, while computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3), this pathogenic evidence code (PP3) was not considered to be in conflict with a likely benign conclusion given the accuracy of computation prediction tools. 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): PP3, BS1
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000590886	SCV000059497	likely benign	Primary dilated cardiomyopathy	2022-11-03	criteria provided, single submitter	clinical testing	The p.Asp1096Tyr variant in MYH7 has been previously reported in >3 individuals with DCM left ventricular hypertrophy (Hershberger 2008 PMID: 19412328, Helms 2014 PMID: 25031304, LMM data). This variant has also been identified in 0.026% (18/68042) European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as Likely Benign on Mar 22, 2021 by the ClinGen-approved Cardiomyopathy variant curation expert panel (Variation ID 42953). Given the frequency, this variant is classified as likely benign. ACMG/AMP Criteria applied: BS1, PP3.
GeneDx	RCV000656921	SCV000208535	likely benign	not provided	2021-04-26	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23299917, 25163546, 32659924, 22337857, 23403236, 18555187, 27247418, 25031304, 19412328, 26383716, 27688314, 29300372, 28798025, 31737537, 28588093, 32528171, 32880476)
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000201875	SCV000256636	uncertain significance	Hypertrophic cardiomyopathy 1	2015-07-30	criteria provided, single submitter	research	The Asp1096Tyr variant in MYH7 has been previously reported by Hershberger et al (2008) in 2 DCM probands. Helms et al (2014) analysed sarcomere transcript and protein levels in septal myectomy and transplant specimens from genotyped HCM patients - one of whome carried this MYH Asp1096Tyr variant. This variant has been reported with an allele frequency of 0.0001 (18/66,720 European non-Finnish alleles and 1/908 'other') in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). The MYH7 Asp1096Tyr variant occurs in a conserved region, and in-silico tools (SIFT, PolyPhen, MutationTaster and CADD) support a damaging role for this variant, however this alone is not strong evidence for pathogenicity. We have identified this variant in 1 HCM proband who presented in her 30's with asymmetric hypertrophy (IVS 21mm) and obstruction. This proband experienced a sudden cardiac death in her 50s. It is noted that this proband also carried a pathogenic MYBPC3 nonsense variant. Based on the limited reports in the literature, and our finding of MYH7 Asp1096Tyr in an isolated HCM case who carried an additional variant which is known to be disease-causing, we have classified this variant as having "uncertain significance". Additional evidence is required to fully establish its pathogenic role.
Invitae	RCV000529912	SCV000623693	uncertain significance	Hypertrophic cardiomyopathy	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 1096 of the MYH7 protein (p.Asp1096Tyr). This variant is present in population databases (rs45478699, gnomAD 0.03%). This missense change has been observed in individual(s) with cardiomyopathy (PMID: 19412328, 25031304, 25163446, 27247418, 28798025, 29300372). ClinVar contains an entry for this variant (Variation ID: 42953). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. 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.
CSER _CC_NCGL, University of Washington	RCV000590886	SCV000700123	likely pathogenic	Primary dilated cardiomyopathy	2016-10-01	criteria provided, single submitter	research	Found in patient having exome sequencing for an unrelated indication. No known history of dilated cardiomyopathy. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Ambry Genetics	RCV000620264	SCV000736672	likely benign	Cardiovascular phenotype	2021-06-05	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.
Color Diagnostics, LLC DBA Color Health	RCV000758039	SCV000913719	uncertain significance	Cardiomyopathy	2023-01-30	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with tyrosine at codon 1096 of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with cardiomyopathy (PMID: 19412328, 27247418, 25031304, 32659924, 32746648, 32880476). This variant has also been identified in 40/282846 chromosomes (40/129122 non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Although the variant allele frequency is greater than expected for MYH7-related disorders based on prevalence, penetrance, and allelic heterogeneity, the available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen	RCV000656921	SCV001149179	uncertain significance	not provided	2017-01-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000491282	SCV001272028	benign	Dilated cardiomyopathy 1S	2019-05-21	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 rule this variant out of causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001114182	SCV001272029	benign	MYH7-related skeletal myopathy	2019-05-21	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 rule this variant out of causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV003320065	SCV001272030	uncertain significance	Myosin storage myopathy	2019-05-21	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000491282	SCV001440771	uncertain significance	Dilated cardiomyopathy 1S	2019-01-01	criteria provided, single submitter	clinical testing
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	RCV001265537	SCV001443279	uncertain significance	See cases	2020-11-17	criteria provided, single submitter	clinical testing	We observed a genetic variant c.3286G>T (p.D1096Y) in a male 68-y.o. patient diagnosed with left ventricular non-compaction and heart rhythm disorders. The p.D1096Y variant has a frequency of 1.414e-4 in gnomAD. The variant was detected in a MYH7 gene with z-score of 3.93, therefore intolerant to missense variants. Online in silico tools (PolyPhen2, MutationTaster, SIFT) predict the variant to be deleterious. However, in the absence of family screening results and the data on functional effects, we could only classify the p.D1096Y variant as the variant of uncertain clinical significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000758039	SCV002042664	uncertain significance	Cardiomyopathy	2019-10-30	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000656921	SCV003817701	uncertain significance	not provided	2023-03-29	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004534742	SCV004115300	uncertain significance	MYH7-related disorder	2023-03-06	criteria provided, single submitter	clinical testing	The MYH7 c.3286G>T variant is predicted to result in the amino acid substitution p.Asp1096Tyr. This variant has been reported in individuals with dilated cardiomyopathy (Hershberger et al. 2008. PubMed ID: 19412328, Table 2), individuals with hypertrophic cardiomyopathy (Table S2 - Helms et al. 2014. PubMed ID: 25031304; Dataset S1 - Homburger. 2016. PubMed ID: 27247418), and an individual with left ventricular noncompaction (Table S3 - Miszalski-Jamka et al. 2017. PubMed ID: 28798025). However, it has also been reported in presumably healthy controls (Andreasen et al. 2013. PubMed ID: 23299917; Dataset S1 - Homburger. 2016. PubMed ID: 27247418). This variant is reported in 0.031% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-23890217-C-A). In ClinVar, this variant has conflicting interpretations of pathogenicity ranging from benign to uncertain including likely benign by an expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/42953/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV000758039	SCV004814401	uncertain significance	Cardiomyopathy	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with tyrosine at codon 1096 of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with cardiomyopathy (PMID: 19412328, 27247418, 25031304, 32659924, 32746648, 32880476). This variant has also been identified in 40/282846 chromosomes (40/129122 non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Although the variant allele frequency is greater than expected for MYH7-related disorders based on prevalence, penetrance, and allelic heterogeneity, the available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen	RCV000491282	SCV000298099	uncertain significance	Dilated cardiomyopathy 1S	2016-05-01	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000656921	SCV001549878	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MYH7 p.Asp1096Tyr variant was identified in 4 of 1006 proband chromosomes (frequency: 0.00398) from individuals with dilated cardiomyopathy (DCM) or left ventricular non-compaction (LVNC) and was not identified in 506 control chromosomes from healthy individuals (Hershberger_2008_PMID:19412328; Miszalski-Jamka_2017_PMID:28798025). The variant was identified in dbSNP (ID: rs45478699) and ClinVar (classified as uncertain significance by Invitae, Laboratory for Molecular Medicine, ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel and five other laboratories, and classified as likely pathogenic by CSER_CC_NCGL; University of Washington Medical Center). The variant was identified in control databases in 40 of 282846 chromosomes at a frequency of 0.0001414 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the European (non-Finnish) population in 40 of 129162 chromosomes (freq: 0.00031), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The p.Asp1096 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000656921	SCV002034980	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000656921	SCV002037378	uncertain significance	not provided		no assertion criteria provided	clinical testing