Submissions for variant NM_000257.4(MYH7):c.2890G>C (p.Val964Leu)

gnomAD frequency: 0.00050  dbSNP: rs45496496

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171841	SCV000050866	uncertain significance	Primary dilated cardiomyopathy	2018-04-05	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035831	SCV000059482	uncertain significance	not specified	2017-07-06	criteria provided, single submitter	clinical testing	The p.Val964Leu variant in MYH7 has been reported in at least 5 individuals with cardiomyopathy including DCM (3) and HCM (2) (Hershberger et al. 2008, van Spae ndonck-Zwarts et al. 2013, GENetic CORvitia 2009), and has been identified by ou r laboratory in 9 individuals with cardiomyopathy (6 DCM, 3 HCM). Val at positio n 964 is highly conserved in evolution and the change to Leu was predicted to be pathogenic using a computational tool clinically validated by our laboratory. T his tool's pathogenic prediction is estimated to be correct 94% of the time (Jor dan 2011). However, this variant has also been identified in 0.08% (104/126728) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnom ad.broadinstitute.org; dbSNP rs45496496). In summary, the data is somewhat confl icting and therefore, the clinical significance of the p.Val964Leu variant is un certain.
GeneDx	RCV000415867	SCV000208514	likely benign	not provided	2021-06-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23861362, 26220970, 23349452, 25163546, 23299917, 19412328, 22958901, 27247418, 25351510, 27153395, 27600940, 28771489, 24704860, 28807990, 28798025, 31737537, 30847666, 26582918, 27535533, 32880476)
Eurofins Ntd Llc (ga)	RCV000415867	SCV000227877	uncertain significance	not provided	2015-04-10	criteria provided, single submitter	clinical testing
Invitae	RCV000229046	SCV000284272	likely benign	Hypertrophic cardiomyopathy	2024-01-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000277164	SCV000386125	likely benign	MYH7-related skeletal myopathy	2018-05-22	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	RCV000332160	SCV000386126	likely benign	Dilated Cardiomyopathy, Dominant	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000625843	SCV000386127	likely benign	Hypertrophic cardiomyopathy 1	2018-05-22	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	RCV000282513	SCV000386128	likely benign	Dilated cardiomyopathy 1S	2018-05-22	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	RCV003320057	SCV000386129	likely benign	Myosin storage myopathy	2018-05-22	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.
CeGaT Center for Human Genetics Tuebingen	RCV000415867	SCV000493187	uncertain significance	not provided	2023-02-01	criteria provided, single submitter	clinical testing	MYH7: PP2, PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000415867	SCV000696347	uncertain significance	not provided	2017-01-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000618924	SCV000736800	likely benign	Cardiovascular phenotype	2021-08-10	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.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000625843	SCV000746410	likely benign	Hypertrophic cardiomyopathy 1	2023-12-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771360	SCV000903652	uncertain significance	Cardiomyopathy	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces valine with leucine at codon 964 of the MYH7 protein. Computational prediction tool indicates that this variant may have an uncertain impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 19412328, 23349452, 31568572, 35299955) and hypertrophic cardiomyopathy (PMID: 24704860). This variant has also been identified in 124/282890 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although the relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing, 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.
Athena Diagnostics Inc	RCV000415867	SCV001144678	uncertain significance	not provided	2019-03-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000415867	SCV001159819	likely benign	not provided	2021-04-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000771360	SCV002042660	uncertain significance	Cardiomyopathy	2021-10-12	criteria provided, single submitter	clinical testing
Mendelics	RCV000035831	SCV002518337	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000625843	SCV003804692	uncertain significance	Hypertrophic cardiomyopathy 1	2023-01-09	criteria provided, single submitter	clinical testing	Criteria applied: PP2, PP3
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000035831	SCV000280337	uncertain significance	not specified	2015-02-25	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Val964Leu (c.2890G>C) in the MYH7 gene. When the patient first had genetic testing, the variant was novel. Since then it has been seen in at least 12 additional cases of primary cardiomyopathy. The variant was reported in one individual with familial dilated cardiomyopathy and considered possibly pathogenic by the authors (Hershberger et al 2008). Gencor (a national registry with patients and families with a familial heart disease in the Netherlands) reported unpublished data on three patients in two families with the variant; however it is unclear which specific cardiac disease these individuals had (http://www.gencor.nl/gencor/docs/GencorNHJ2009november.pdf). I contacted them directly and they told me they have now seen this variant in four of 831 index HCM cases and an infant with LVNC. This is a conservative amino acid change with a nonpolar Valine replaced with a nonpolar Leucine. Valine is completely conserved at this position in the MYH7 gene, as are nearby residues. SIFT predicts the variant to be tolerated, while PolyPhen predicts it to be possibly damaging. A sarcomere-specific prediction tool that is estimated to be correct 94% of the time predicts the variant to be pathogenic (Jordan et al 2011). Additional variants associated with disease have been reported in nearby codons: p.Leu961Arg (Haluza et al 2001) and p.Asp953His (van Driest et al 2004). Hershberger et al (2008) did not find p.Val964Leu in 253 presumably healthy controls (188 Caucasian, 24 African American, 22 Asian and 19 Hispanic) Correlagen did not provide control data on this variant. GeneDx told me they did not observe the variant in 300 control individuals of various ethnicities. The variant is listed in dbSNP (rs45496496) with genotype frequency data from a general population sample from Coriell, noting the variant was absent in 231 individuals of various ethnicities. In addition, dbSNP notes that the variant was observed (ss342383782) in two of 2276 individuals studied through the NHLBI GO exome sequencing project (ESP), which consists of various large well-phenotyped cohorts (ex. WHI, Framingham, Jackson Heart Study, ARIC, CARDIA). No phenotypic information about the individuals who had this variant is provided. None of the cohorts listed were specific to HCM, though with their large sample sizes individuals with HCM likely would have been included due to chance alone. Thus, in total, the variant has been reported in 2 of 2960 general population individuals.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000415867	SCV001553832	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MYH7 p.Val964Leu variant was identified in 3 of 1082 proband chromosomes (frequency: 0.0028) from individuals with dilated or hypertrophic cardiomyopathy (Maurizi_2018_PMID:29710196, Claes_2015_PMID:26497160, van-Spaendonck-Zwarts_2013_PMID:23349452). The variant was identified in dbSNP (ID: rs45496496) and ClinVar (classified as uncertain significance by GeneDx and nine other submitters, as likely benign by Invitae and two other submitters, and as likely pathogenic by Genomic Research Genter Shahid Beheshti University of Medical Sciences). The variant was identified in control databases in 124 of 282890 chromosomes at a frequency of 0.0004383 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 109 of 129196 chromosomes (freq: 0.000844), South Asian in 13 of 30616 chromosomes (freq: 0.000425) and Latino in 2 of 35440 chromosomes (freq: 0.000056), but was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), or Other populations. The p.Val964 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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.
Genomics England Pilot Project, Genomics England	RCV000625843	SCV001760332	likely pathogenic	Hypertrophic cardiomyopathy 1		no assertion criteria provided	clinical testing