ClinVar Miner

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

gnomAD frequency: 0.00002  dbSNP: rs387907267
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 23
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham 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Deprez 2006, Foksteun 2008, Morita 2008, Michels 2009, Van Driest 2004, Ta jsharghi 2010, Yiu 2012, Wessels 2014, LMM unpublished data).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 2022-06-03 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies using cardiomyocytes derived from induced pluripotent stem cells demonstrated this variant activates the nonsense-mediated decay pathway and results in aberrant calcium signaling and dysregulation of a set of other cardiac genes (Seeger et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19666645, 23674513, 25335496, 26026863, 18761664, 22569109, 28214152, 30731207, 31006259, 31918855, 31513939, 30847666, 32480058, 22574137, 16679492, 25525159, 26936621, 15519027, 19858127, 27532257, 23396983, 24510615, 22857948, 24111713, 28794111, 28396031, 28005231, 23233322, 20624503, 21839045, 19356534, 19574547, 30165862, 28797094, 29447731, 30742251, 31323898, 33673806, 32665702, 33662488, 32746448, 20505798, 30586709)
Center for Medical Genetics Ghent, University of Ghent RCV000030699 SCV000299253 pathogenic Hypertrophic cardiomyopathy 4 2016-01-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000248559 SCV000319955 pathogenic Cardiovascular phenotype 2021-09-24 criteria provided, single submitter clinical testing The p.R943* pathogenic mutation (also known as c.2827C>T) located in coding exon 27 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 2827. This changes the amino acid from an arginine to a stop codon within coding exon 27. This mutation has been reported in multiple unrelated probands with hypertrophic cardiomyopathy, having been reported as a Dutch founder mutation (Van Driest SL et al. J Am Coll Cardiol. 2004; 44(9):1903-10; Michels M et al. Neth Heart J. 2007;15(5):184-90; Michels M et al. JACC Cardiovasc Imaging. 2009;2(1):58-64; Christiaans I et al. Neth Heart J. 2010;18(5):248-54; Brito D et al. Rev Port Cardiol. 2012;31(9):577-87; Hathaway J et al. BMC Cardiovasc Disord, 2021 03;21:126). This mutation has been reported as occurring in the homozygous state and also with other alterations in patients with severe, early onset disease with and without other findings such as skeletal myopathy, non-compaction and congenital heart defects (Lekanne Deprez RH et al. J Med Genet. 2006;43(10):829-32; Tajsharghi H et al. J Med Genet. 2010;47(8):575-7; Berge KE et al. Clin Genet. 2014;86(4):355-60; Wessels MW et al. Eur J Hum Genet. 2015;23(7):922-8; van Velzen HG et al. Circ Cardiovasc Genet, 2017 Aug;10:[Epub ahead of print]). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000471886 SCV000546480 pathogenic Hypertrophic cardiomyopathy 2024-01-04 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg943*) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is present in population databases (rs387907267, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 19574547, 20505798, 20624503, 22574137, 22857948, 23233322, 24111713, 25335496). It is commonly reported in individuals of Dutch ancestry (PMID: 19574547, 20505798, 20624503, 22574137, 22857948, 23233322, 24111713, 25335496). ClinVar contains an entry for this variant (Variation ID: 37039). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000030699 SCV000743547 pathogenic Hypertrophic cardiomyopathy 4 2014-10-08 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000030699 SCV000744834 pathogenic Hypertrophic cardiomyopathy 4 2015-09-21 criteria provided, single submitter clinical testing
Royal Brompton Clinical Genetics And Genomics Laboratory, NHS South East Genomic Laboratory Hub 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
Color Diagnostics, LLC DBA Color Health RCV001179578 SCV001344272 pathogenic Cardiomyopathy 2023-12-18 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 27 of the MYBPC3 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Functional RNA studies using cardiac tissue derived from a heterozygous carrier individual have shown that this variant causes a significant reduction in MYBPC3 mRNA levels (PMID: 33757590). This variant has been observed in over 20 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 16679492, 20624503, 22857948, 23233322, 24111713, 25335496, 27532257, 31006259, 31513939, 33757590, 36252119, 36835444) and is considered to be a founder mutation in the Dutch population (PMID: 20505798, 28794111). This variant has been reported to cause lethal cardiomyopathy or severe neonatal hypertrophic cardiomyopathy in individuals who were homozygous or compound heterozygous with another pathogenic mutation (PMID: 16679492, 24111713, 25335496, 30742251, 36178741). It has also been reported in two individuals affected with left ventricular noncompaction who both carried an additional different pathogenic variant (PMID: 31918855, 37963751), and in one individual affected with atrioventricular block (PMID: 35470684). This variant has been identified in 3/247124 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000158189 SCV001480055 pathogenic not provided 2021-02-01 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001179578 SCV002042176 pathogenic Cardiomyopathy 2021-05-28 criteria provided, single submitter clinical testing
3billion RCV000030699 SCV002521399 pathogenic Hypertrophic cardiomyopathy 4 2022-05-22 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000037039 / PMID: 14563344 / 3billion dataset). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
MGZ Medical Genetics Center RCV000030699 SCV002580166 pathogenic Hypertrophic cardiomyopathy 4 2022-06-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001179578 SCV003844999 pathogenic Cardiomyopathy 2023-02-20 criteria provided, single submitter clinical testing Variant summary: MYBPC3 c.2827C>T (p.Arg943X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.2e-05 in 247124 control chromosomes (gnomAD). c.2827C>T has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (e.g. Van Driest_2004, Deprez_2006, Michels_2007, Berge_2013). These data indicate that the variant is very likely to be associated with disease. 15 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000030699 SCV000053360 pathogenic 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 Hypertrophic cardiomyopathy 4 no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000158189 SCV001808627 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000158189 SCV001919644 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000158189 SCV001955474 pathogenic not provided no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000158189 SCV002035736 pathogenic not provided no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.