Submissions for variant NM_000256.3(MYBPC3):c.2454G>A (p.Trp818Ter)

dbSNP: rs397515965

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000461443	SCV000059140	pathogenic	Hypertrophic cardiomyopathy	2015-01-26	criteria provided, single submitter	clinical testing	The p.Trp818X variant in MYBPC3 has been reported in 2 individuals with HCM (Mil ler 2013, Adalsteinsdottir 2014), and was absent from large population studies. This variant has also been identified by our laboratory in 4 Caucasian individua ls with HCM and segregated with disease in 1 affected relative. This nonsense va riant leads to a premature termination codon at position 818, which is predicted to lead to a truncated or absent protein. Heterozygous loss-of-function of the MYBPC3 gene is an established disease mechanism in individuals with HCM. In summ ary, this variant meets our criteria to be classified as pathogenic for HCM in a n autosomal dominant manner (http://www.partners.org/personalizedmedicine/LMM) b ased on the predicted impact of the variant.
GeneDx	RCV000158150	SCV000208085	pathogenic	not provided	2022-06-06	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; A different nucleotide change (c.2453 G>A) leading to the same nonsense variant has been reported as pathogenic at GeneDx and in published literature in association with HCM (PMID: 25078086); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25078086, 27532257, 23054336, 24793961, 32659924, 33906374)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000461443	SCV000546407	pathogenic	Hypertrophic cardiomyopathy	2024-12-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp818*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 42622). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222364	SCV002500544	pathogenic	Primary familial hypertrophic cardiomyopathy	2022-03-21	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.2454G>A (p.Trp818X) 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 was absent in 249246 control chromosomes. c.2454G>A has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (example, Miller_2013, Walsh_2017, Kolokotronis_2020). These data indicate that the variant is very likely to be associated with disease. Three 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. Based on the evidence outlined above, the variant was classified as pathogenic.
All of Us Research Program, National Institutes of Health	RCV000461443	SCV004828379	pathogenic	Hypertrophic cardiomyopathy	2023-07-07	criteria provided, single submitter	clinical testing	The c.2454G>A (p.Trp818*) variant in MYBPC3 creates a premature termination codon. It is predicted to cause a truncated or absent MYBPC3 protein due to nonsense mediated decay. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant has been identified in multiple unrelated individuals with hypertrophic cardiomyopathy (HCM) (PMID: 27532257, 32659924). This variant is absent in the general population (gnomAD). Based on these evidence, the c.2454G>A (p.Trp818*) variant in MYBPC3 is classified as pathogenic.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000158150	SCV000280239	pathogenic	not provided	2012-01-18	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Trp818Stop (c.2454 G>A) in the MYBPC3 gene. See report below. Given the amount of unrelated affected individuals and the mechanism of disease for MYBPC3, (reviewed below) we consider this variant likely disease causing. This variant has been previously reported in at least six, possibly seven unrelated cases (not including our patient). Per their ClinVar entry, this variant has been reported in 4 unrelated caucasian individuals at the Laboratory for Molecular Medicine (LMM) with HCM and family history or HCM. No additional details were provided. LMM classifies this variant as pathogenic. This was also reported in a two year old patient who was also heterozygous for a missense mutation in the MYL3 gene (Miller, et al., 2013). The group noted that this variant was inherited from a parent, however no information was provided about the parent. The group analyzed the following genes: MYH7, TNNT2, TPM1, MYBPC2, TNNI3, MYL2, MYL3, ACTC, TTR, TNNC1, CAV3, LAMP2, GLA, PRKAG2, MTTC, MTTI, MTTK, LMNA, ZAS/LDB3, DES, SGCD, PLN, ACTC1, TNNI2, TAZ, TTR, MTTL1, MTTQ, MTTH, MTTS1, MTTS2, MTND1, MTND5, and MTND6. However, testing was done clinically so this may overlap with one of the LMM cases. Ackerman's group observed the variant in an individual in their cohort of 1053 unrelated patients with HCM who underwent DHLPC-based analysis of 9 sarcomere genes at Mayo (Bos et al 2014). This variant was identified in an Icelandic male who was diagnosed at 33 yo with no prior family history of HCM. His maximal LV thickness was 28 mm.The patient had no history of AF, HTN, CAD or ICD. He had undergone an eight sarcomeric gene panel targeted for HCM. They referred to this variant as likely pathogenic (Adalsteinsdottir, et al. 2014). This nonsense variant creates a premature stop codon. The variant is expected to either cause a truncated protein or a completely absent protein due to nonsense-mediated mRNA decay. Many other frameshift and nonsense 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). In total the variant has not been seen in 6200 published controls and individuals from publicly available population datasets. There is no variation at codon 818 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on 6400 Caucasian and African American individuals (as of October 21, 2014). dbSNP and 1000 genomes both direct to the LMM data listed above (as of October 21, 2014).