ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2890G>C (p.Val964Leu) (rs45496496)

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Total submissions: 20
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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 RCV000171841 SCV000050866 uncertain significance Primary dilated cardiomyopathy 2018-04-05 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare 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)
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000415867 SCV000227877 uncertain significance not provided 2015-04-10 criteria provided, single submitter clinical testing
Invitae RCV000229046 SCV000284272 likely benign Hypertrophic cardiomyopathy 2020-12-07 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000277164 SCV000386125 likely benign Myopathy, distal, 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). 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 Clinical Services Laboratory,Illumina RCV000332160 SCV000386126 likely benign Dilated Cardiomyopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000625843 SCV000386127 likely benign Familial 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 Clinical Services Laboratory,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 Clinical Services Laboratory,Illumina RCV000337581 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 Praxis fuer Humangenetik Tuebingen RCV000415867 SCV000493187 uncertain significance not provided 2018-08-01 criteria provided, single submitter clinical testing
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 uncertain significance Cardiovascular phenotype 2019-06-06 criteria provided, single submitter clinical testing The p.V964L variant (also known as c.2890G>C), located in coding exon 21 of the MYH7 gene, results from a G to C substitution at nucleotide position 2890. The valine at codon 964 is replaced by leucine, an amino acid with highly similar properties. This variant has been described in dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), left ventricular non-compaction (LVNC), and arrhythmia cohorts; however, in some cases, clinical details were limited or this variant was seen in conjunction with alterations in other cardiac-related genes (Hershberger RE et al. Clin Transl Sci. 2008;1:21-6, Lopes LR et al. Heart. 2015;101:294-301; Pugh TJ et al. Genet Med. 2014;16:601-8, van Spaendonck-Zwarts KY et al. Eur J Heart Fail. 2013;15:628-36; Di Resta C et al. Hum Mol Genet. 2015;24:5828-35; Homburger JR et al. Proc Natl Acad Sci U.S.A., 2016 06;113:6701-6; Claes GR et al. Eur Heart J. 2016;37:1815-22; Miszalski-Jamka K et al. Circ Cardiovasc Genet, 2017 Aug;10:[Epub ahead of print]). This alteration also has been seen in exome cohorts (Andreasen C et al. Eur J Hum Genet. 2013;21(9):918-28; Ng D et al. Circ Cardiovasc Genet. 2013;6(4):337-46). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000625843 SCV000746410 likely pathogenic Familial hypertrophic cardiomyopathy 1 2017-12-03 criteria provided, single submitter clinical testing
Color Health, Inc RCV000771360 SCV000903652 uncertain significance Cardiomyopathy 2020-11-17 criteria provided, single submitter clinical testing This missense variant replaces valine with leucine at codon 964 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 individuals affected with dilated cardiomyopathy (PMID: 19412328, 23349452, 31568572) 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 RCV000035831 SCV001159819 likely benign not specified 2018-07-13 criteria provided, single submitter clinical testing
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 Familial hypertrophic cardiomyopathy 1 no assertion criteria provided clinical testing

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