ClinVar Miner

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

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Total submissions: 17
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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 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 RCV000035831 SCV000208514 uncertain significance not specified 2017-03-27 criteria provided, single submitter clinical testing The V964L variant of uncertain significance in the MYH7 gene has been reported previously in association with cardiomyopathy (Hershberger et al., 2008; van Spaendonck-Zwarts et al., 2013; Ng et al., 2013; Captur et al., 2014; Haas et al., 2015). Hershberger et al. (2008) identified the V964L variant in an individual with familial DCM; however, segregation studies in affected family members were not performed. van Spaendonck-Zwarts et al. (2013) reported V964L in one patient with idiopathic DCM, but V964L did not meet the study's criteria for classification as a pathogenic variant (co-segregation, phenotypic features and/or functional analysis, and absence in controls).While this substitution occurs at a position that is conserved across species, the V964L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, the Exome Aggregation Consortium (ExAC) reports V964L was observed in 43/66,740 (0.06%) alleles from individuals of European (Non-Finnish) ancestry. Finally, the V964L variant was also observed in one individual without cardiovascular disease in the offspring cohort of the Framingham Heart Study (Bick et al., 2012).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000415867 SCV000227877 uncertain significance not provided 2015-04-10 criteria provided, single submitter clinical testing
Invitae RCV000229046 SCV000284272 uncertain significance Hypertrophic cardiomyopathy 2018-05-01 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 964 of the MYH7 protein (p.Val964Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. This variant is present in population databases (rs45496496, ExAC 0.06%). This variant has been reported in individuals affected with dilated cardiomyopathy and hypertrophic cardiomyopathy (PMID: 19412328, 23349452, 24503780, 24704860, 26497160). ClinVar contains an entry for this variant (Variation ID: 42938). A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). 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.
Illumina Clinical Services Laboratory,Illumina RCV000277164 SCV000386125 likely benign Myopathy, distal, 1 2016-06-14 criteria provided, single submitter clinical testing
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 RCV000229046 SCV000386127 likely benign Hypertrophic cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000282513 SCV000386128 likely benign Left ventricular noncompaction cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000337581 SCV000386129 likely benign Myosin storage myopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000378228 SCV000386130 likely benign Scapuloperoneal myopathy 2016-06-14 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000415867 SCV000493187 uncertain significance not provided 2016-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000415867 SCV000696347 uncertain significance not provided 2017-01-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000618924 SCV000736800 uncertain significance Cardiovascular phenotype 2017-04-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
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 RCV000771360 SCV000903652 uncertain significance Cardiomyopathy 2018-10-08 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the neck and hinge region (S2 domain) of the MYH7 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 19412328, 23349452) and hypertrophic cardiomyopathy (PMID 24704860). This variant has also been identified in 118/277240 chromosomes (104/126728 non-Finnish European chromosomes, 0.082%) in the general population by the Genome Aggregation Database (gnomAD). Although the relatively high frequency of this variant in the general population suggests that it is unlikely to be disease-causing, available evidence is insufficient to rule out the pathogenicity of this variant conclusively.
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.

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