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

gnomAD frequency: 0.00001  dbSNP: rs397515966

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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variant in MYBPC3 has been observed in at least 4 individuals wit h HCM (Van Driest 2004, Kapplinger 2014, LMM unpublished data) and segregated wi th disease in 1 affected relative (LMM unpublished data).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, http://exac.broadinstitute.org; 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: //www.partners.org/personalizedmedicine/LMM) based on the predicted impact of th e variant.
GeneDx	RCV000158365	SCV000208300	pathogenic	not provided	2024-11-11	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.2490_2491insT and S830 fs/1; Frameshift 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; This variant is associated with the following publications: (PMID: 21839045, 24510615, 29237689, 27532257, 33673806, 31980526, 33190526, 37652022, 35653365, 34542152, 15519027)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000232323	SCV000284227	pathogenic	Hypertrophic cardiomyopathy	2024-12-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.His831Serfs*2) 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 (rs397515966, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 15519027, 21839045). ClinVar contains an entry for this variant (Variation ID: 42625). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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
Clinical Genetics Laboratory, Region Ostergotland	RCV002251731	SCV002522542	likely pathogenic	Hypertrophic cardiomyopathy 4	2022-04-04	criteria provided, single submitter	clinical testing	PVS1, PS4, PP5
Mayo Clinic Laboratories, Mayo Clinic	RCV000158365	SCV005413979	pathogenic	not provided	2023-08-18	criteria provided, single submitter	clinical testing	PM2, PS4_moderate, PVS1
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 (http://exac.broadinstitute.org/), 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).