Submissions for variant NM_000256.3(MYBPC3):c.2182G>T (p.Glu728Ter)

dbSNP: rs397515954

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000768471	SCV000059121	pathogenic	Hypertrophic cardiomyopathy	2018-06-04	criteria provided, single submitter	clinical testing	The p.Glu728X variant in MYBPC3 has been identified in 3 individuals with HCM an d segregated with disease in 3 affected relatives (LMM data). It was absent from large population databases. This nonsense variant leads to a premature terminat ion codon at position 728, which is predicted to lead to a truncated or absent p rotein. Heterozygous loss of function of the MYBPC3 gene is an established disea se mechanism in HCM. In summary, this variant meets our criteria to be classifie d as pathogenic based on predicted impact on the protein, absence from controls, case observations, and segregation in affected family members. ACMG/AMP Criteri a applied: PVS1, PM2, PP1, PS4_Supporting.
GeneDx	RCV000158141	SCV000208076	pathogenic	not provided	2023-06-12	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; Identified in patients with HCM referred for genetic testing at GeneDx and in published literature (Forleo et al., 2017; Walsh et al., 2017; Weissler-Snir et al., 2017; Robyns et al., 2020; Park et al., 2022); at least one patient harbored an additional cardiogenetic variant; Identified in a patient with fetal cardiomyopathy who also harbored another pathogenic variant in the MYBPC3 gene, though phase was unknown (Trakmulkichkarn et al., 2022); both MYBPC3 variants were identified in this individual's sibling who died of SIDS with cardiac enlargement; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24810389, 27532257, 34542152, 28193612, 19574547, 28750076, 31513939, 34159662)
Center for Human Genetics, University of Leuven	RCV000768471	SCV000886757	pathogenic	Hypertrophic cardiomyopathy	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000768471	SCV001417126	pathogenic	Hypertrophic cardiomyopathy	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu728*) 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 clinical features of hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 42605). For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798083	SCV002042154	pathogenic	Cardiomyopathy	2019-08-27	criteria provided, single submitter	clinical testing