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A heterozygous missense variant in LDB3 was identified in a family with arrhythmogenic right ventricular cardiomyopathy. Next-generation sequencing of the index case revealed c.1051A>G (p.Thr351Ala), confirmed by Sanger sequencing, and six additional first- and second-degree relatives were carriers, of whom three met definitive ARVC criteria and one a borderline diagnosis (PMID:25041374).
No ARVC-specific functional assays for LDB3 p.Thr351Ala have been reported. Although Cypher/ZASP isoforms are developmentally regulated in cardiac muscle and LDB3 knockout is neonatal lethal in mice, there is no direct mechanistic evidence linking this variant to ARVC.
Key Take-home: LDB3 c.1051A>G (p.Thr351Ala) shows segregation in a single family with ARVC but requires replication and functional validation before clinical implementation.
Gene–Disease AssociationLimitedSingle family with one heterozygous LDB3 missense variant segregating in six carriers (three definitive ARVC, one borderline); no replication cohorts Genetic EvidenceLimitedAutosomal dominant inheritance; one proband and six carriers; three additional affected relatives segregating c.1051A>G (p.Thr351Ala) ([PMID:25041374]) Functional EvidenceLimitedNo direct ARVC-specific functional studies of p.Thr351Ala; general LDB3/Cypher knockout data are non-specific to ARVC |