Submissions for variant NM_000256.3(MYBPC3):c.3811C>T (p.Arg1271Ter)

gnomAD frequency: 0.00001  dbSNP: rs397516042

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000475268	SCV000059270	pathogenic	Hypertrophic cardiomyopathy	2019-07-03	criteria provided, single submitter	clinical testing	The p.Arg1271X variant in MYBPC3 gene has been identified in 6 individuals with HCM and segregated with disease in 1 affected family member (Olivotto 2008, Marston 2009, Lopes 2013, Walsh 2017, LMM data). It was also identified in 1 individual with early onset DCM who carried an additional pathogenic variant in MYBCP3 (LMM data). It has been identified in 2/246124 chromosomes by gnomAD (https://gnomad.broadinstitute.org) and reported in ClinVar (Variation ID #42744). This nonsense variant leads to a premature termination codon at position 1271, which is predicted to lead to a truncated or absent protein. Loss of function of the MYBCP3 gene is an established disease mechanism in autosomal dominant HCM. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate.
GeneDx	RCV000158271	SCV000208206	pathogenic	not provided	2024-01-26	criteria provided, single submitter	clinical testing	Identified in individuals with HCM referred for genetic testing at GeneDx and in published literature (PMID: 18533079, 23396983, 28254189, 27532257, 30297972, 31110529); Reported in one patient with early onset familial DCM requiring heart transplantation at age 3, who also harbored the p.(Q404*) variant in trans (PMID: 19996403); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation, as the last 4 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Functional studies demonstrate a damaging effect with reduced MYBPC3 protein in a myomectomy sample from an individual with this variant (PMID: 19574547); This variant is associated with the following publications: (PMID: 36264615, 23396983, 25524337, 25525159, 18533079, 30297972, 27532257, 28254189, 31110529, 31589614, 33673806, 33087929, 33996946, 25351510, 34076677, 35626289, 36129056, 19996403, 19574547)
Blueprint Genetics	RCV000208264	SCV000264044	likely pathogenic	Primary familial hypertrophic cardiomyopathy	2015-02-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000475268	SCV000546415	pathogenic	Hypertrophic cardiomyopathy	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1271*) in the MYBPC3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 4 amino acid(s) of the MYBPC3 protein. This variant is present in population databases (rs397516042, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 18533079, 23396983, 33673806; Invitae). ClinVar contains an entry for this variant (Variation ID: 42744). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MYBPC3 function (PMID: 19574547). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000515345	SCV000611211	pathogenic	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2017-05-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000621330	SCV000740206	pathogenic	Cardiovascular phenotype	2022-08-26	criteria provided, single submitter	clinical testing	The p.R1271* pathogenic mutation (also known as c.3811C>T), located in coding exon 33 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 3811. This changes the amino acid from an arginine to a stop codon within coding exon 33. This alteration occurs at the 3' terminus of theMYBPC3 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 4 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration has been reported in individuals with hypertrophic cardiomyopathy (Olivotto I et al. Mayo Clin. Proc., 2008 Jun;83:630-8; Marston S et al. Circ. Res., 2009 Jul;105:219-22; Judge DP. JAMA, 2009 Dec;302:2471-6; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852435	SCV000995120	pathogenic	Long QT syndrome; Hypertrophic cardiomyopathy	2018-06-05	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170942	SCV001333593	pathogenic	Cardiomyopathy	2023-03-22	criteria provided, single submitter	clinical testing
3billion	RCV001807752	SCV002058836	pathogenic	Hypertrophic cardiomyopathy 4	2022-01-03	criteria provided, single submitter	clinical testing	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_S). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000042744, PMID:18533079). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001170942	SCV002074311	pathogenic	Cardiomyopathy	2022-01-17	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.3811C>T (p.Arg1271X) 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 associated with hypertrophic cardiomyopathy in HGMD and have been cited as pathogenic in ClinVar. The variant allele was found at a frequency of 8.1e-06 in 246124 control chromosomes (gnomAD). c.3811C>T has been reported in the literature in individuals affected with hypertrophic cardiomyopathy (examples: Martson_2009, Coppini_2014, Ho_2018, Hathaway_2021). These data indicate that the variant is likely to be associated with disease. Experimental evidence demonstrated absence of the expected truncated protein and significantly lower quantity of MyBP-C in myofibrils compared with non-failing donor heart muscle, as determined in myectomy sample(s) with the variant (Martson_2009). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=6) / likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001170942	SCV004358619	pathogenic	Cardiomyopathy	2023-11-29	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 33 of the major myosin binding region of the MYBPC3 gene, creating a premature translation stop signal in the C-terminus region. This variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. A functional study using myomectomy samples from a carrier individual have shown reduced protein expression levels (PMID: 19574547). This variant has been reported in over 10 individuals affected with hypertrophic cardiomyopathy (PMID: 18533079, 19574547, 23396983, 25524337, 27532257, 30297972, 31110529, 33495596; communication with external laboratories: ClinVar SCV000208206.13, SCV000059270.6). It has also been reported in one individual suspected to be affected with hypertrophic cardiomyopathy (PMID: 33673806), in one individual affected with cardiomyopathy (PMID: 28254189), and in homozygous state in one child affected with hypertrophic cardiomyopathy (DOI:10.32592/psj.21.3.194). A splicing variant occurring downstream of this variant is known to be disease-causing (ClinVar variation ID: 42746). This variant has been identified in 2/246124 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000158271	SCV005199305	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing