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Atrial standstill is a rare arrhythmogenic disorder characterized by the absence of atrial electrical and mechanical activity, leading to increased risk of sudden death. Familial cases are infrequently reported, and isolated mutations in SCN5A have seldom been described in this phenotype. Two key studies provide the principal evidence linking SCN5A variants to atrial standstill.
In a consanguineous family, a novel homozygous SCN5A p.Val1340Leu variant was identified in two sisters presenting with complete and partial atrial standstill, respectively; heterozygous parents and sibling had normal sinus rhythm and were asymptomatic (PMID:29781517).
In a large pedigree of 44 individuals, a heterozygous SCN5A D1275N (NM_000335.5:c.3820G>A (p.Asp1274Asn)) mutation cosegregated with a rare connexin40 genotype in three living atrial standstill patients; unaffected relatives carrying only the SCN5A variant remained asymptomatic (PMID:12522116).
The inheritance pattern for isolated homozygous p.Val1340Leu cases is consistent with autosomal recessive transmission. Across both reports, five affected individuals have been documented, including two homozygotes and three compound‐genotype carriers. Variant spectrum remains limited to missense changes without frameshifts or truncations.
Functional studies in HEK293 cells demonstrate that Nav1.5(V1340L) channels exhibit markedly reduced current density and a depolarizing shift in voltage‐dependent activation, while Asp1274Asn channels show similar but milder activation shifts, consistent with a loss‐of‐function mechanism. These biophysical alterations correlate with failure to initiate atrial action potentials.
Collectively, these observations support a Moderate level of clinical validity for SCN5A in isolated atrial standstill. Additional case series and segregation data are needed to reach a higher level of evidence. Key Take-home: Biallelic loss-of-function SCN5A mutations can underlie autosomal recessive atrial standstill and inform genetic testing strategies in affected families.
Gene–Disease AssociationModerateTwo homozygous probands and three additional affected relatives; functional loss-of-function data concordant Genetic EvidenceModerateTwo homozygous p.V1340L probands (AR) and a separate family with SCN5A D1275N segregating in three relatives Functional EvidenceModeratePatch-clamp assays show reduced Nav1.5 current density and depolarizing activation shifts for V1340L and Asp1274Asn variants |