ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2490dup (p.His831fs) (rs397515966)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000232323 SCV000059143 pathogenic Hypertrophic cardiomyopathy 2015-02-04 criteria provided, single submitter clinical testing The p.His831fs variant in MYBPC3 has been observed in at least 4 individuals wit h HCM (Van Driest 2004, Kapplinger 2014, LMM unpublished data) and segregated wi th disease in 1 affected relative (LMM unpublished data). This variant has also been identified in 3/66680 of European chromosomes by the Exome Aggregation Cons ortium (ExAC,; dbSNP rs397515966). Please note th at for diseases with clinical variability and reduced penetrance, pathogenic var iants may be present at a low frequency in the general population. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequen ce beginning at position 831 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or ab sent protein. Heterozygous loss of function of function of the MYBPC3 gene is an established disease mechanism in HCM. In summary, this variant meets our criter ia to be classified as pathogenic for HCM in an autosomal dominant manner (http: // based on the predicted impact of th e variant.
Blueprint Genetics RCV000157328 SCV000207064 likely pathogenic Primary familial hypertrophic cardiomyopathy 2015-11-10 criteria provided, single submitter clinical testing
GeneDx RCV000158365 SCV000208300 pathogenic not provided 2018-12-03 criteria provided, single submitter clinical testing The c.2490dupT pathogenic variant in the MYBPC3 gene has previously been reported in association with HCM (denoted S830 fs/1 using alternate nomenclature) (Van Driest et al., 2004; Kapplinger et al., 2014) and it was absent from more than 1,200 control alleles, collectively. In addition, the c.2490dupT variant has been identified in other unrelated individuals referred for HCM genetic testing at GeneDx.The c.2490dupT pathogenic variant causes a shift in reading frame starting at codon Histidine 831, changing it to a Serine, and creating a premature stop codon at position 2 of the new reading frame, denoted p.His831SerfsX2. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Multiple other downstream frameshift variants in the MYBPC3 gene have been reported in HGMD in association with HCM (Stenson et al., 2014). Furthermore, the c.2490dupT variant has not been observed in large population cohorts (Lek et al., 2016).
Invitae RCV000232323 SCV000284227 pathogenic Hypertrophic cardiomyopathy 2019-10-27 criteria provided, single submitter clinical testing This sequence change inserts 1 nucleotide in exon 25 of the MYBPC3 mRNA (c.2490dupT), causing a frameshift at codon 831. This creates a premature translational stop signal (p.His831Serfs*2) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic. This particular truncation has been reported in the literature in two individuals affected with hypertrophic cardiomyopathy (PMID: 15519027, 21839045). This variant is also known in the literature as c.2490_2491insT. For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000157328 SCV000919807 pathogenic Primary familial hypertrophic cardiomyopathy 2018-10-01 criteria provided, single submitter clinical testing Variant summary: MYBPC3 c.2490dupT (p.His831SerfsX2) 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. The variant allele was found at a frequency of 1.2e-05 in 246844 control chromosomes. c.2490dupT has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (VanDriest 2004 Maron 2012, Kapplinger 2014, Walsh 2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (3x) / likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.
Blueprint Genetics RCV000158365 SCV000928062 pathogenic not provided 2018-11-20 criteria provided, single submitter clinical testing
Clinical Genetics Laboratory,Skane University Hospital Lund RCV000232323 SCV001132777 pathogenic Hypertrophic cardiomyopathy 2019-12-16 criteria provided, single submitter clinical testing ACMG criteria met: PVS1, PS4
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000158365 SCV000924851 likely pathogenic not provided 2016-05-27 no assertion criteria provided provider interpretation c.2490dupT (p.His831Serfs*2) in the MYBPC3 gene Given the fact that this is a loss of function variant in a gene where loss of function is a well-established mechanism of disease and a moderate amount of case data, we consider this variant to be likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). We have seen the variant in an individual with HCM. The variant has been seen in at least 3 unrelated cases of HCM (not including this patient's family). This is moderate case data. It has been reported in 2 cases in the literature. Van Driest et al., 2004 reported the variant using alternative nomenclature (S830 fs/1) in a patient with HCM. Maron et al., 2012 reported the variant in a series of compound heterozygote patients. The patient had HCM and this variant as well as a MYH7 Arg1832Cys variant. This frameshift variant is expected to result in a truncated or absent protein product because of nonsense mediated mRNA decay. Loss of function is an established mechanism of disease in the MYBPC3 gene. The variant was reported online in 3 of 60,340 individuals in the Exome Aggregation Consortium dataset (, which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 5/26/16). Specifically, the variant was observed in 3 of 33,340 non-Finnish European people. 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).

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.