ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2827C>T (p.Arg943Ter) (rs387907267)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000471886 SCV000059178 pathogenic Hypertrophic cardiomyopathy 2015-10-01 criteria provided, single submitter clinical testing The p.Arg943X variant in MYBPC3 has been reported in >25 individuals with HCM an d segregated with disease in 4 affected relatives in 4 families (Alders 2003, Le kanne Deprez 2006, Foksteun 2008, Morita 2008, Michels 2009, Van Driest 2004, Ta jsharghi 2010, Yiu 2012, Wessels 2014, LMM unpublished data). Several of these i ndividuals carried an additional clinically significant variant and presented wi th early onset disease. This variant has also been identified in 1/16138 South A sian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadins titute.org; dbSNP rs387907267). This nonsense variant leads to a premature termi nation codon at position 943, which is predicted to lead to a truncated or absen t protein. Nonsense and other MYBPC3 variants resulting in a heterozygous loss o f function are strongly associated with HCM. In summary, this variant meets our criteria to be classified as pathogenic for HCM in an autosomal dominant manner (http://www.partners.org/personalizedmedicine/LMM) based upon segregation studie s and predicted impact on the protein.
GeneDx RCV000158189 SCV000208124 pathogenic not provided 2018-11-30 criteria provided, single submitter clinical testing The R943X pathogenic variant in the MYBPC3 gene has been reported several times in association with HCM (Van Driest et al., 2004; Michels et al., 2009; Brito et al., 2012; Lopes et al., 2013; Witjas-Paalberends et al., 2013; Kapplinger et al., 2014; Walsh et al., 2017). It is also been published as a founder mutation in the Dutch population (Christiaans et al., 2010). Additionally, this variant has been identified in multiple probands with infantile-onset cardiomyopathy who were reportedly either homozygous for the R943X variant, or compound heterozygous for R943X and another truncating variant in the MYBPC3 gene (Lekanne Deprez et al., 2006; Tajsharghi et al., 2010; Berge et al., 2014; Wessels et al., 2015). Moreover, R943X has been observed to segregate with HCM in multiple affected heterozygous relatives from unrelated families (Wessels et al., 2015).The R943X pathogenic variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Multiple other nonsense variants in the MYBPC3 gene have been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014). Furthermore, several other clinical laboratories have reported R943X as a pathogenic variant in ClinVar (ClinVar SCV000059178.4, SCV000219774.2, SCV000299253.1, SCV000319955.1, SCV000546480.1; Landrum et al., 2016). Finally, this variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Center for Medical Genetics Ghent,University of Ghent RCV000030699 SCV000299253 pathogenic Familial hypertrophic cardiomyopathy 4 2016-01-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000248559 SCV000319955 pathogenic Cardiovascular phenotype 2017-05-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000471886 SCV000546480 pathogenic Hypertrophic cardiomyopathy 2018-11-15 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 943 (p.Arg943*) of the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. Truncating variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This particular variant has been observed in unrelated individuals with hypertrophic cardiomyopathy (PMID: 22574137, 23233322, 25335496, 24111713, 22857948, 20624503) and is considered a founder mutation in the Dutch population (PMID: 20505798). ClinVar contains an entry for this variant (Variation ID: 37039). For these reasons, this variant has been classified as Pathogenic.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000030699 SCV000743547 pathogenic Familial hypertrophic cardiomyopathy 4 2014-10-08 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000030699 SCV000744834 pathogenic Familial hypertrophic cardiomyopathy 4 2015-09-21 criteria provided, single submitter clinical testing
RBHT Clinical Genetics and Genomics Laboratory,Royal Brompton and Harefield NHS Foundation Trust RCV000471886 SCV000845659 pathogenic Hypertrophic cardiomyopathy 2017-10-04 criteria provided, single submitter clinical testing This variant has been reported in mutiple unrelated HCM patients in the literature (refs 1-6, below), and has also been shown to segregate with disease in multiple affected individuals in several unrelated families (Wessels et al (2015) Eur J Hum Genet 23(7)922-928). Several other clinical laboraties have also detected the variant in HCM patients referred for genetic testing (ClinVar variation ID: 37039). The variant has also been detected in control populations at a very low frequency which is compatible with the prevalence of disease (ExAC and gnomAD databases). In view of the evidence, this variant is pathogenic. - References - 1. Alders et al. (2003) Eur Heart J. 24(20):1848-53. 2. Van et al. (2004) J Am Coll Cardiol. 44(9):1903-10. 3. Christiaans et al. (2010) Neth Heart J. 18(5):248-54. 4. Millat et al. (2010) Eur J Med Genet. 53(5):261-7. 5. Yiu et al. (2012) PLoS One. 7(5):e36115. 6. Alfares et al. (2015) Genet Med.17(11):880-8. - Population Controls alleles / total (frequency): Exome Aggregation Consortium (ExAC) - 2/117632 (0.00001700), RBH healthy cohort - 0/2144 (0.0)
Center for Human Genetics,University of Leuven RCV000471886 SCV000886766 pathogenic Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000158189 SCV000927931 pathogenic not provided 2018-09-13 criteria provided, single submitter clinical testing
OMIM RCV000030699 SCV000053360 pathogenic Familial hypertrophic cardiomyopathy 4 2010-08-01 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000158189 SCV000280245 pathogenic not provided 2017-04-27 no assertion criteria provided provider interpretation p.Arg943Stop in the MYBPC3 gene. In total the variant has been seen in at least 18 unrelated cases with weak segregation data. This variant was initially reported in Van Driest S et al. (2004) in one individual with HCM, in the presence of another missense variant (S166F) in the TNNI3 gene (note: p.S166F in TNNI3 is also currently considered a likely disease-causing variant). The authors noted that this patient, among the other 9 with multiple mutations identified, had significantly younger age of diagnosis, the most hypertrophy, and the highest incidence of myectomy and ICD placement when compared with single mutation carriers. This variant was absent from 200 control individuals screened in their study (100 African Americans and 100 European Americans). Michels et al. 2007 reports this p.Arg943Stop variant as a Dutch founder mutation, present in 15 of 100 Netherland families with HCM. Michels et al. 2009 subsequently reports this p.Arg943Stop variant in a study performing echocardiograms in genotyped HCM patients (8 of 27 with this particular variant), mutation carriers without LVH (7 of 27 family members), and 55 controls (this variant was present in 0 of 55 controls). Note, it is unclear whether these are overlapping with the 100 families reported in this group's 2007 study. Christiaans et al. 2010 also reports this variant as a founder mutation in the Netherlands. Tajsharghi et al. 2010 reports this variant seen in homozygous form in an infant with fatal cardiomyopathy and skeletal myopathy. The patient expressed the cardiac specific MyBPC isoform in skeletal muscle at transcript and protein levels. This was a similar finding in Deprez et al. 2005, where p.Arg943Stop was identified in a neonate with severe unexplained HCM who died within the first few weeks of life, in trans with a frameshift MYBPC3 variant. GeneDx reports that this variant has also been seen in multiple other unrelated individuals tested at GeneDx. This variant also segregates with disease in the patient's own family (as it is present in him, his father, and his aunt (all of whom have HCM)). This is a nonsense variant predicted to cause loss of normal protein function either through premature protein truncation or nonsense-mediated mRNA decay. Many other truncating or null variants have been identified in MYBPC3 in association with cardiomyopathy (ex. p.Trp792fs, p.Pro794fs, p.Lys1065fs, p.Cys1202fs, p.Pro1208fs, p.Trp1098ter, p.Glu1096ter, p.Cys1124ter, p.Gln1233ter). Furthermore, these types of variants in MYBPC3 are not seen in individuals without cardiomyopathy (Pan et al 2012). The variant was reported online in 3 of 122,257 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 2 of 15,313 individuals of South Asian descent (MAF=0.006%) and 1 of 55,460 individuals of European descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012).
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000030699 SCV000733034 pathogenic Familial hypertrophic cardiomyopathy 4 no assertion criteria provided clinical testing

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