ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.772G>A (p.Glu258Lys) (rs397516074)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000205517 SCV000059319 pathogenic Hypertrophic cardiomyopathy 2016-08-23 criteria provided, single submitter clinical testing The p.Glu258Lys variant in MYBPC3 has been reported in many HCM probands and seg regated in additional affected family members (Girolami 2006, Marston 2009, Niim ura 1998, Nanni 2003, Olivotto 2008, LMM data). It has been identified in 3/4334 8 European chromosomes by the Exome Aggregation Consortium (http://exac.broadins; dbSNP rs397516074); however, for diseases with clinical variability , reduced penetrance, or recessive inheritance, pathogenic variants may be prese nt at a low frequency in the general population. This variant affects the last b ase of exon 6, which is part of the splice consensus sequence. This alteration w as shown to affects splicing, leading to skipping of exon 6, which is predicted to result in a frameshift, premature termination and therefore likely in a loss of function (Anderson 2004). Heterozygous loss of MYBPC3 function is an establis hed mechanism of HCM, which further supports a pathogenic role of the p.Glu258Ly s variant. In summary, this variant meets criteria to be classified as pathogeni c for autosomal dominant HCM based on presence in many affected individuals, seg regation with disease, low allele frequency in the general population, and obser ved impact on splicing.
Blueprint Genetics RCV000035668 SCV000188783 pathogenic Primary familial hypertrophic cardiomyopathy 2015-09-07 criteria provided, single submitter clinical testing
GeneDx RCV000158310 SCV000208245 pathogenic not provided 2017-02-28 criteria provided, single submitter clinical testing The E258K pathogenic variant in the MYPBC3 gene has been reported in multiple unrelated patientswith HCM (Niimura et al., 1998; Richard et al., 2003; Nanni et al., 2003; Van Driest et al., 2004; Songet al., 2005; Murphy et al., 2016). The E258K variant results in a change of charge at a highlyconserved position in cardiac myosin-binding protein C (cMyBP-C) and alters the last base of exon 6,immediately 5' of the canonical GT" of the splice donor site. In silico analysis with three differentsplice algorithms predicts that this splice donor site in intron 6 is either abolished or its quality issignificantly reduced, leading to aberrant gene splicing. Furthermore, functional studies havedemonstrated that the E258K variant creates a truncated protein product due to skipping of exon 6,which results in rapid protein product degradation and impairs ubiquitinproteasome system capacity(Sarikas et al., 2005; Helms et al., 2014). The E258K variant has also been shown by De Lange et al.(2013) to accelerate contractile kinetics, disrupt twitch force and abolish the interaction betweencMyBP-C and myosin heavy chain sub-fragment 2 in murine engineered cardiac tissue. The E258Kvariant was not observed in approximately 6,200 individuals of European and African Americanancestry in the NHLBI Exome Sequencing Project, and was not observed with any significantfrequency in the Exome Aggregation Consortium (ExAC) data set. In summary, E258K in the MYBPC3 gene is interpreted as a pathogenic variant."
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000158310 SCV000231501 pathogenic not provided 2015-04-03 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000161125 SCV000256170 likely pathogenic Familial hypertrophic cardiomyopathy 4 criteria provided, single submitter clinical testing
Invitae RCV000205517 SCV000260690 pathogenic Hypertrophic cardiomyopathy 2018-12-29 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 258 of the MYBPC3 protein (p.Glu258Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant also falls at the last nucleotide of exon 6 of the MYBPC3 coding sequence. This variant is present in population databases (rs397516074, ExAC <0.01%). This variant was reported in many individuals and families affected with hypertrophic cardiomyopathy (HCM) (PMID: 9562578, 12707239, 15563892, 18533079, 20031602, 22267749, 23233322). This is a common variant among HCM patients in Italy, being identified in 21% of the cases studied (PMID: 18533079). This variant is also known as E264K in the literature. ClinVar contains an entry for this variant (Variation ID: 42792). Experimental studies using cardiomyocytes and engineered cardiac tissue have shown that this missense change abolishes the interaction of MYBPC3 with the myosin heavy chain and causes the misincorporation of MYBPC3 to Z-discs, resulting in significantly accelerated twitch kinetics and reduction in force production (PMID: 15769446, 23980194). Nucleotide substitutions at the last nucleotide of the exon are relatively common causes of aberrant splicing (PMID: 17576681). Experimental studies using lymphocytes and septal myectomy samples from patients have shown that this change leads to the out-of-frame skipping of exon 6 of the MYBPC3 gene (PMID: 15114369, 19574547, 25031304). The homozygous knock-in mouse for p.Glu258Lys recapitulates some of the features present in HCM patients, such as left ventricular hypertrophy and reduced fractional shortening (PMID: 19590044). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000247227 SCV000320235 pathogenic Cardiovascular phenotype 2017-09-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Functionally-validated splicing mutation,Last nucleotide of exon,Rarity in general population databases (dbsnp, esp, 1000 genomes),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Phosphorus, Inc. RCV000161125 SCV000679779 pathogenic Familial hypertrophic cardiomyopathy 4 2017-08-01 criteria provided, single submitter clinical testing
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000161125 SCV000693449 pathogenic Familial hypertrophic cardiomyopathy 4 2017-05-09 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000161125 SCV000744867 pathogenic Familial hypertrophic cardiomyopathy 4 2015-09-21 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000035668 SCV000747994 pathogenic Primary familial hypertrophic cardiomyopathy 2016-12-20 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763244 SCV000893880 pathogenic Familial hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000035668 SCV000917820 pathogenic Primary familial hypertrophic cardiomyopathy 2017-12-12 criteria provided, single submitter clinical testing Variant summary: The MYBPC3 c.772G>A (p.Glu258Lys) variant involves the alteration of a conserved nucleotide located just one nucleotide upstream from an exon-intron junction. 3/5 in silico tools predict a damaging outcome for this variant. 5/5 programs via Alamut predict that this variant affects normal splicing. Multiple functional studies confirmed that the variant leads to exon 6 skipping resulting in a premature stop codon (Anderson_2004, Helms_2014). Heterozygous loss-of-function due to mutations in the MYBPC3 gene is an established disease mechanism in HCM. This variant was found in 5/270526 control chromosomes at a frequency of 0.0000185, which does not exceed the estimated maximal expected allele frequency of a pathogenic MYBPC3 variant (0.0010005). The variant has been recurrently found in numerous patients with HCM and is reported to cosegregate with the disease (Niimura_1998; Girolami_2006). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000205517 SCV000996340 pathogenic Hypertrophic cardiomyopathy 2017-03-21 criteria provided, single submitter research The MYBPC3 Glu258Lys is a rare variant, with an allele frequency of 0.000039 in the Exome Aggregation Consortium dataset ( This variant has been reported in multiple unrelated HCM patients (see references), and is observed to be shared in up to ~14% of unrelated HCM cases in Italian cohorts, suggesting a founder effect (Girolami et al, 2006; Olivotto et al, 2008). Segregation analyses support its pathogenic role (Niimura et al., 1998; Girolami et al., 2006). In silico tools (SIFT, PolyPhen-2, MutationTaster) predict this variant to be disease causing. Furthermore, this variant affects the splice site consensus sequence (last base of exon 6) and has been shown to result in truncated MYBPC3 protein due to exon skipping (Anderson et al., 2004; Sarikas et al., 2005; Helms AS, et al., 2014). Functional studies have shown that the truncated protein is incorporated into cardiac sarcomeres and impairs contractile function (De Lange et al., 2013). We have identified MYBPC3 Glu258Lys in 3 HCM probands. In summary, based on rarity in the general population, observation in multiple unrelated HCM cases and because loss of function is a mechanism of disease for MYBPC3, we classify this variant as "pathogenic".
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000161125 SCV000733061 pathogenic Familial hypertrophic cardiomyopathy 4 no assertion criteria provided clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000158310 SCV000924856 pathogenic not provided 2015-10-28 no assertion criteria provided provider interpretation

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