ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000003.11) (NC_000003.12)
  • Haploinsufficiency score: 2
  • Strength of Evidence (disclaimer): Some evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
19279983 In Tfelt-Hansen et al. (2009) the authors characterize a SCN5A frameshift mutation (c.3480delT) that causes a truncation of the SCN5A protein product. This mutation was identified in a 28 year old male who presented with Brugada syndrome, as well as his unaffected mother and a maternal uncle with a history of hypertension. This mutation was not identified in 100 control individuals. To examine the functional consequence of this mutation, the authors performed a series of in vitro transfection assays in HEK293 (human embryonic kidney) cells. These transfection assays demonstrated that the SCN5A mutant protein had a significant decrease in expression level as well as a decrease in channel activity. Based on these results the authors suggest that this mutation is associated with a haploinsufficient-type mechanism.
17399644 Two frameshift nonsense mutations have been described that likely lead to haploinsufficiency in SCN5A causing Brugada syndrome. Makita et al (2007, PMID 17399644) described a 17 y.o. male with Brugada syndrome. He was identified to have a novel SCN5A mutation at exon 2 resulting in a premature stop codon, Q55X. His mother and brother were both identified to have the same mutation. His mother had sick sinus syndrome with first-degree AV block and his asymptomatic brother had first-degree AV block and nonspecific intraventricular conduction delay. Kapplinger et al (2010, PMID 20129283) presented a retrospective database analysis of SCN5A mutations from 9 international centers. They had one patient who also had a premature stop codon in exon 2 at Q73X. Given that both of these mutations are nonsense mutations very close to the N-terminus before the first transmembrane domain, they are highly likely to cause haploinsufficiency. At this time, a complete deletion of SCN5A has not been described in association with Brugada syndrome.

Haploinsufficiency phenotype comments:

SCN5A encodes a subunit (type V, alpha) of a voltage-gated sodium channel protein that functions in cardiac muscle to regulate conduction. More than 600 SCN5A variants have been reported in association with cardiac channelopathy phenotypes. Heterozygous sequence-level mutations in SCN5A are associated with a number of cardiovascular abnormalities including Brugada syndrome, cardiac conduction disease (CCD), long QT syndrome type 3 (LQT3), atrial fibrillation, and sick sinus syndrome (SSS). Functional studies (patch clamp assays, cellular localization studies, and western blots) have been performed on a number of the reported mutations; however, these studies have been done in in vitro models and it is unknown whether these mutations would have the same functional consequence in vivo. To this point, one study on SCN5A variants stated that ?caution should be taken when extrapolating the findings from the in vitro study of HEK293 cells and oocytes to the more complex in vivo conditions? (Gui et al. 2010). Based on the functional studies mentioned above, SCN5A loss-of-function-type mutations have been associated with Brugada syndrome, CCD, and SSS, while SCN5A gain-of-function-type mutations have been associated with LQT3 (Hong et al., 2005; Makiyama et al., 2005; Zimmer and Surber, 2008; Kapplinger et al. 2010; Eastaugh et al., 2011; Remme 2013). Both loss-of-function and gain-of-function-type mutations of SCN5A have been identified in association with atrial fibrillation (Remme, 2013). Incomplete penetrance for some of the SCN5A mutant phenotypes has also been observed (Cordeiro et al., 2006; Makita et al., 2007; Eastaugh et al., 2011). Although there are a number of SCN5A mutations that are reported to be associated with loss-of-function-type mechanism (Tfelt-Hansen et al. 2009), the SCN5A genotype/phenotype association is still not well understood as there are several mutations that have been associated with both Brugada syndrome (loss-of-function) and LQT3 (gain-of-function) (Zimmer and Surber et al., 2008; Blich et al. 2015). Due to the clinical heterogeneity, mutational spectrum, and lack of reports of whole gene deletions, the haploinsufficiency score is a 1.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

Triplosensitivity of SCN5A has not been reported.