ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.655G>C (p.Val219Leu) (rs397516068)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000232070 SCV000059311 likely pathogenic Hypertrophic cardiomyopathy 2015-10-29 criteria provided, single submitter clinical testing The p.Val219Leu variant in MYBPC3 has been reported in >15 individuals with HCM and segregated with disease in one affected relative (Van Driest 2004, Pan 2012, Kaski 2012, LMM data). It has not been identified in large population studies. This variant is located in the first base of the exon, which is part of the 3? splice region. Computational splicing prediction tools do not predict altered sp licing. In vitro studies showed that this variant results in skipping of exon 6 (Crehalet 2012), which is predicted to cause a frameshift and a premature termin ation codon, leading to a truncated or absent protein. However, these types of o f prediction tools and assays may not accurately represent biological function. In summary, although additional segregation and in vivo studies are required to fully establish its clinical significance, the p.Val219Leu variant is likely pat hogenic.
GeneDx RCV000158303 SCV000208238 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In vitro studies by Crehalet et al. (2012) have shown that the c.655 G>C substitution results in skipping of exon 6, which is expected to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation.; Occurs at the first exonic nucleotide of exon 6, which is a part of the splice acceptor site; At the mRNA level, in silico splice algorithms predict this variant reduces the efficiency of the natural splice acceptor site in intron 5 of the MYBPC3 gene, which may cause abnormal gene splicing; Other splice site variants in the MYBPC3 gene have been reported in HGMD in association with HCM (Stenson et al., 2014), including a pathogenic variant at the same nucleotide position (c.655 G>T) that also causes exon 6 skipping (Crehalet et al., 2012), supporting the functional significance of this nucleotide; Reported in ClinVar as pathogenic or likely pathogenic (ClinVar Variant ID# 42784; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 21415409, 23782526, 27532257, 15519027, 30645170, 23074333, 24510615, 23690394, 23396983, 20031602, 26914223, 20031618, 20624503, 29540445, 22589294, 25351510, 28790153, 28679633, 28087566)
Invitae RCV000232070 SCV000284250 pathogenic Hypertrophic cardiomyopathy 2020-10-26 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 219 of the MYBPC3 protein (p.Val219Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 15519027, 20624503, 20031618, 20031602, 26914223). ClinVar contains an entry for this variant (Variation ID: 42784). Experimental studies have shown that this missense change causes skipping of exon 6 (Crehalet 2012, http://dx.doi.org/10.4081/cardiogenetics.2012.e6). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000617271 SCV000740158 pathogenic Cardiovascular phenotype 2019-03-05 criteria provided, single submitter clinical testing The c.655G>C pathogenic mutation (also known as p.V219L) is located in coding exon 6 of the MYBPC3 gene. This variant results from a G to C substitution at nucleotide position 655. The valine at codon 219 is replaced by leucine, an amino acid with highly similar properties. This change occurs in the first base pair of coding exon 6. This mutation has been reported in a number of individuals in hypertrophic cardiomyopathy (HCM) cohorts (e.g., Van Driest SL et al. J. Am. Coll. Cardiol. 2004;44:1903-10; Kapplinger JD et al. J Cardiovasc Transl Res. 2014;7:347-61; Lopes LR et al. J. Med. Genet. 2013;50:228-39; Walsh R et al. Genet. Med. 2017;19:192-203). In addition, this alteration causes complete skipping of exon 6 in an in vitro minigene assay (Crehalet H et al. Cardiogenetics. 2012;2:e6; Ito K et al. Proc. Natl. Acad. Sci. U.S.A., 2017 07;114:7689-7694). Skipping of exon 6 is expected to lead to a frameshift with a predicted alternative stop (p.V219Rfs*42). A likely pathogenic variant in the same nucleotide, c.655G>T, reported to lead to skipping of exon 6 has also been associated with HCM (Millat G et al. Eur J Med Genet. 2010;53:261-7; Crehalet H et al. Cardiogenetics. 2012;2:e6). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000158303 SCV000747993 pathogenic not provided 2017-07-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000035660 SCV000917816 pathogenic Primary familial hypertrophic cardiomyopathy 2021-01-07 criteria provided, single submitter clinical testing Variant summary: MYBPC3 c.655G>C (p.Val219Leu) results in a conservative amino acid change located in the Immunoglobulin-like domain (IPR007110) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, experimental evidence suggests that the variant causes complete skipping of exon 6 (Crehalet_2012). The variant was absent in 246060 control chromosomes (gnomAD). c.655G>C has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (example: VanDriest_2004, Lopes_2013, Seidelmann_2017, Miller_2019). These data indicate that the variant is very likely to be associated with disease. Eight other ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Blueprint Genetics RCV000158303 SCV000927446 pathogenic not provided 2017-10-23 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170211 SCV001332763 pathogenic Cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV001537862 SCV001754766 pathogenic Familial hypertrophic cardiomyopathy 4 2020-03-19 criteria provided, single submitter clinical testing The c.655G>C (p.Val219Leu) variant in the MYBPC3 gene has been reported in multiple unrelated patients with hypertrophic cardiomyopathy (HCM) (PMID: 15519027, 20624503, 20031618, 20031602, 23782526, 24510615, 26914223). This variant is absent from general population databases. It is located at the first nucleotide of exon 6 of the MYBPC3 gene and predicted to affect the RNA splicing. Functional studies have showed that the c.655G>C change causes skipping of exon 6, which is predicted to result in a truncated protein or absence of the protein (Crehalet et al., 2012). In summary, this c.655G>C (p.Val219Leu) in the MYBPC3 gene is classified as pathogenic.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000158303 SCV000280277 likely pathogenic not provided 2014-12-07 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. Val219Leu (c.655G>C) in exon 6 of the MYBPC3 gene (NM_000256.3) Given case data and functional studies we consider this variant likely disease causing. The variant has been seen in at least 15 unrelated cases of HCM (not including this patient). None of the studies below reported segregation data. The variant has been reported in multiple cases in the literature (Van Driest et al 2004, Kaski et al 2009, Ho et al 2009, Nunez et al 2013). Crehalet et al (2012) demonstrated that p.Val219Leu leads to complete skipping of exon 6. Many other variants in MYBPC3 that affect splicing have been implicated in cardiomyopathy. This is a conservative amino acid change with a nonpolar Valine replaced with a nonpolar Leucine at residue 219. Two variants at nearby residues of the variant (p.Asp228Asn and p.Gln208His) and another variant at the same residue (p.Val219Phe, Crehalet et al 2012) have been reported in association with HCM (CardioGenomics http://genepath.med.harvard.edu/ ). The Valine at codon 219 is highly, though not completely conserved (there is an Isoleucine in frogs). Of note, the variant affects the first base of exon 6, which is part of the splicing consensus sequence (and is most frequently a G). The Laboratory for Molecular Medicine performed in silico analysis with the program NNSplice and found the variant is predicted to affect splicing. In total this variant has not been seen in ~7500 published controls, laboratory controls, and publicly available general population samples. The variant was not observed in an internal sample of 400 presumably healthy controls of various ancestries at Familion Labs. Van Driest et al (2004) did not observe the variant in 100 Caucasian and 100 African American controls. Kaski et al (2009) did not identify the variant in 200 presumably healthy individuals of unspecified racial descent. GeneDx did not observe the variant in 400 Caucasian and African American controls. The variant is not currently listed in dbSNP or 1000 genomes and the variant is not listed in the NHLBI exome sequencing project, which currently includes data on ~4200 European Americans and ~2100 African Americans (as of March 10, 2015). There is one variation at codon 219 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~47,500 individuals of European, African, Latino and Asian descent (as of March 10, 2015). The amino acid substitution reported in exac was different, p.Val219Phe.
NIHR Bioresource Rare Diseases, University of Cambridge RCV001251034 SCV001426427 likely pathogenic Asymmetric septal hypertrophy 2018-01-01 no assertion criteria provided research
Genomics England Pilot Project,Genomics England RCV001537862 SCV001760268 likely pathogenic Familial hypertrophic cardiomyopathy 4 no assertion criteria provided clinical testing

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