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In a large consanguineous Chinese family with eight carriers of the MYBPC3 c.3624delC (p.Lys1209SerfsTer28) pathogenic variant, a heterozygous CACNB2 c.1598C>T (p.Ser533Leu) variant was identified exclusively in severely affected hypertrophic cardiomyopathy patients and was absent in 550 ethnically matched healthy controls (PMID:28614222). This missense change affects a highly conserved residue in the β2 subunit of the L-type calcium channel, suggesting a modifier role in MYBPC3-associated HCM rather than a primary causative effect.
To date, no unrelated probands with CACNB2 variants have been reported in HCM cohorts, and no cellular or animal model has been used to demonstrate a direct impact of p.Ser533Leu on calcium currents or myocardial hypertrophy. The current evidence is limited to a single family segregation study without functional validation, defining a preliminary and unconfirmed gene–disease link that warrants replication and mechanistic experiments to support diagnostic use. Key Take-home: CACNB2 c.1598C>T (p.Ser533Leu) is a candidate genetic modifier of MYBPC3-related HCM pending further genetic and functional demonstration.
Gene–Disease AssociationLimitedSingle consanguineous family; variant segregates with severe phenotype in MYBPC3 carriers; no unrelated probands Genetic EvidenceLimitedOne heterozygous missense variant segregated with severity in a single family; absent in 550 healthy controls ([PMID:28614222]) Functional EvidenceLimitedNo cellular or animal functional assays reported; only conservation and absence in controls |