Submissions for variant NM_000256.3(MYBPC3):c.999C>G (p.Tyr333Ter)

dbSNP: rs367947846

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154309	SCV000203969	pathogenic	Hypertrophic cardiomyopathy	2015-10-29	criteria provided, single submitter	clinical testing	The p.Tyr333X variant in MYBPC3 has been reported in 3 individuals with HCM, seg regated with disease in 1 affected relative from 1 family (Kassem 2013, LMM unpu blished data) and was absent from large population studies. This nonsense varian t leads to a premature termination codon at position 333, which is predicted to lead to a truncated protein. Heterozygous loss of function of the MYBPC3 gene is an established disease mechanism in HCM. In summary, this variant meets our cri teria to be classified as pathogenic for HCM in an autosomal dominant manner.
Ambry Genetics	RCV000242648	SCV000318860	pathogenic	Cardiovascular phenotype	2013-08-09	criteria provided, single submitter	clinical testing	The p.Y333X pathogenic mutation, located in coding exon 12 of the MYBPC3 gene, results from a C to G substitution at nucleotide position 999. This changes the amino acid from a tyrposine to a stop codon within coding exon 12. This alteration was identifed in 1 of 192 unrelated Egyptians with a clinical diagnosis of hypertrophic cardiomyopathy (Kassem Hsh etal. J Cardiovasc Transl Res. 2013;6:65-80). Futhermore, haploinsufficiency of MYBPC3 has been indicated as a mechanism of disease, causing hypertrophic cardiomyopathy (Marston et al. 2012 J Muscle Res Cell Motil 33:75-80). In addition to the data presented in the literature, premature stop codons are typically deleterious in nature and interpreted as disease-causing mutations (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med 2008;10:294). Based on the supporting evidence, p.Y333X is interpreted as a pathogenic mutation.
GeneDx	RCV000414122	SCV000490637	pathogenic	not provided	2023-04-10	criteria provided, single submitter	clinical testing	Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 177706; ClinVar); Not observed in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 31006259, 25611685, 27532257)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769355	SCV000900743	pathogenic	Cardiomyopathy	2022-10-28	criteria provided, single submitter	clinical testing
Invitae	RCV000154309	SCV001208925	pathogenic	Hypertrophic cardiomyopathy	2023-10-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr333*) 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 individual(s) with hypertrophic cardiomyopathy (PMID: 23233322, 25351510, 25611685). ClinVar contains an entry for this variant (Variation ID: 177706). For these reasons, this variant has been classified as Pathogenic.