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Autosomal dominant transmission of CAPN3-related limb-girdle muscular dystrophy (LGMDD4) has been described in two independent kindreds carrying the recurrent c.759_761del (p.Lys254del) variant in CAPN3. Both families presented with camptocormia, progressive proximal weakness, myalgia, back pain and elevated creatine kinase levels, but heterozygous carriers of the same variant in recessive LGMDR1 pedigrees were asymptomatic, indicating incomplete penetrance or the requirement for additional modifier factors ([PMID:38299438]). This limited genetic evidence, with only two probands and absence of segregation in obligate carriers, yields a Limited clinical validity classification. No functional studies have specifically evaluated the p.Lys254del variant in a dominant context, and pathogenicity remains unconfirmed.
Gene–Disease AssociationLimited2 probands, no segregation in heterozygous carriers, incomplete penetrance undermining causality ([PMID:38299438]) Genetic EvidenceLimitedSingle recurrent variant c.759_761del (p.Lys254del) identified in two LGMDD4 families but heterozygous carriers in recessive families are asymptomatic ([PMID:38299438]) Functional EvidenceLimitedNo functional studies specific to the p.Lys254del variant in a dominant context |