ClinVar Miner

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

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Total submissions: 10
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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 2017-01-25 criteria provided, single submitter clinical testing The V219L pathogenic variant in the MYBPC3 gene has been reported in multiple individuals with either aconfirmed or suspected diagnosis of HCM (Van Driest et al., 2004; Kaski et al., 2009; Nunez et al. 2013; Kapplingeret al. 2014), and has been identified in multiple individuals referred for HCM genetic testing at GeneDx. In addition,V219L was not observed in approximately 6,300 individuals of European and African American ancestry in theNHLBI Exome Sequencing Project, indicating it is not a common variant in these populations. In silico splicingalgorithms predict c.655 G>C (V219L) damages the natural splice acceptor site in intron 5 of the MYBPC3 gene.Furthermore, in vitro functional studies have shown that the c.655 G>C substitution results in skipping of exon 6(Crehalet et al., 2012), which is expected to lead to either a truncated protein product or total absence of protein fromthat allele. In summary, V219L in the MYBPC3 gene is interpreted as a pathogenic variant.
Invitae RCV000232070 SCV000284250 pathogenic Hypertrophic cardiomyopathy 2019-12-17 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, 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 Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;RNA Studies;Well-characterized mutation at same position;Significant disease association in appropriately sized case-control study(ies);Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000158303 SCV000747993 pathogenic not provided 2017-07-03 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000035660 SCV000917816 pathogenic Primary familial hypertrophic cardiomyopathy 2017-10-30 criteria provided, single submitter clinical testing Variant summary: This c.655G>C (p.Val219Leu) variant affects the first exonic nucleotide of exon 6 resulting in amino acid change from Val to Leu. 3/4 in-silico tools predict this variant to be damaging. 3/5 in silico tools via Alamut predict it to affect normal splicing. In addition, ESEfinder also predicts an effect on binding sites for ESE. These prediction results are supported by a functional study the variant causes complete exon 6 skipping (Crehalet 2012), strongly suggesting a pathogenic outcome. This variant is absent from control dataset of gnomAD (~238630chrs tested). This variant has been found in several HCM patients or subjects sought for genetic testing with evidence of cosegregation. Multiple reputable clinical labs as well as databases classify this variant as pathogenic/likely pathogenic. Taken together, this variant has been classified as a Disease Variant (or 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
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 ). 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 (, 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

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