Submissions for variant NM_000256.3(MYBPC3):c.2541C>G (p.Tyr847Ter)

dbSNP: rs397515974

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000629027	SCV000059154	pathogenic	Hypertrophic cardiomyopathy	2020-09-28	criteria provided, single submitter	clinical testing	The c.2541C>A p.Tyr847X variant in MYBPC3 has been reported in 1 individual with hypertrophic cardiomyopathy (HCM; Alfares 2015 PMID: 25611685; Walsh 2017 PMID: 27532257; LMM data) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 847, which is predicted to lead to a truncated or absent protein. Loss of function of the MYBPC3 gene is an established disease mechanism in autosomal dominant HCM. Another variant at this position resulting in the same impact on the protein (c.2541C>G, p.Tyr847X) has been identified in individuals with HCM and is classified as pathogenic by this laboratory as well as others (ClinVar Variation ID 42636). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PVS1, PM2, PS1.
GeneDx	RCV000158167	SCV000208102	pathogenic	not provided	2022-06-21	criteria provided, single submitter	clinical testing	Not observed at significant frequency 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; A different nucleotide substitution (c.2541 C>A) predicted to result in the same nonsense variant (p.(Y847*)) has also been reported in HGMD in association with hypertrophic cardiomyopathy (HGMD); This variant is associated with the following publications: (PMID: 34598319, 25525159, 24510615, 15519027, 24111713, 21415409, 28450932, 24093860, 29121657, 28193612, 31919335, 33673806, 35626289, 32041989)
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000035504	SCV000256185	likely pathogenic	Hypertrophic cardiomyopathy 4		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000629027	SCV000749937	pathogenic	Hypertrophic cardiomyopathy	2024-11-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr847*) 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 variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 42636). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV000158167	SCV000927926	pathogenic	not provided	2018-09-11	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798084	SCV002042170	pathogenic	Cardiomyopathy	2021-03-09	criteria provided, single submitter	clinical testing