Dilated Cardiomyopathy

Gene: SCN5A

Green List (high evidence)

DEFINITIVE by ClinGen:
SCN5A was first reported in relation to autosomal dominant dilated cardiomyopathy (DCM) in 2005 (Olson et al., 2005, PMID: 15671429). Human genetic evidence supporting this gene-disease relationship includes case-level data and segregation data. Numerous variants (missense, frameshift, nonsense) have been reported in humans with isolated DCM (Olson et al., 2005, PMID: 15671429; Ge et al., 2008, PMID: 19808398; McNair et al., 2011, PMID: 21596231; Morales et al., 2011, PMID: 20458009; Grosselin-Badaroudine et al., 2012, PMID: 22675453; Laurent et al., 2012, PMID: 22766342; Mann et al., 2012, PMID: 22999724; Zakrzewska-Koperska et al., 2018, PMID: 29871609; Calloe et al., 2018, PMID: 29506689; Gigli et al., 2019, PMID: 31514951; Doisne et al., 2020, PMID: 31930659). This gene-disease association is supported by mouse models, a human iPS cell culture model, and expression studies. SCN5A mRNA levels were markedly decreased in heart tissues obtained from DCM patients (Kepenek et al., 2019, PMID: 31520233). The myosin heavy chain-Snail transgenic mice displayed a DCM phenotype with conduction block and marked reduction of SCN5A expression (Hesse, et al., 2007, PMID: 17512504). Heterozygous and homozygous knock-in mouse models harboring SCN5A p.D1275N displayed a DCM phenotype including intraventricular conduction block with marked reduction of cardiac sodium currents (Watanabe et al., 2011, PMID: 21824921). Furthermore, patient-derived human iPS cell-induced cardiomyocytes carrying SCN5A p.R219H showed reduced contraction, prolonged action potential duration, early afterdepolarization, and H+-leak currents (Moreau et al., 2018, PMID: 30218094).

Created: 26 Mar 2021, 9:14 a.m. | Last Modified: 26 Mar 2021, 9:14 a.m.

Panel Version: 0.101

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Cardiomyopathy, dilated, 1E, MIM# 601154

Publications

• 15671429
• 15671429
• 19808398
• 21596231
• 20458009
• 22675453
• 22766342
• 22999724
• 29871609
• 29506689
• 31514951
• 31930659
• 31520233
• 17512504
• 21824921
• 30218094