ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000003.11) (NC_000003.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
30193851 Berthome et al, 2018. All exons of SCN5A were sequenced in 1613 patients with Brugada syndrome enrolled in this study. At least 29 loss of function variants were identified in this cohort of patients, including 13 frameshift mutations (c.3667delG, p.Ala1223Profs*7; c.4299delG, p.Tyr1434Metfs*29; c.5356_5357delCT, p.Leu1786Glufs*2; c.1983_1993dup, p.Ala665Glyfs*16; c.2559delT, p.Phe853Leufs*16; c.5314delC, p.Leu1772Trpfs*15; c.5417_5420del, p.Thr1806Serfs*27; c.2172del, p.Met725Cysfs*17; c.5461del, p.Leu1821Cysfs*13; c.3931_3932del, p.Leu1311Glufs*7; c.2942_2951dup, p.Arg986Trpfs*47; c.4231del, p.Ala1411Profs*52; c.617del, p.Thr206Lysfs*22) 15 nonsense mutations (c.1603C>T, p.Arg535*; c.3622G>T, p.Glu1208*; c.4178T>A, p.Leu1393*; c.5083C>T, p.Gln1695*; c.664C>T, p.Arg222*; c.2998C>T, p.Gln1000*; p.Tyr1755*; c.535C>T, p.Arg179*; c.217C>T, p.Gln73*; c.145G>T, p.Glu49*; c.4885C>T, p.Arg1629*; c.1036G>T, p.Glu346*; c.127C>T, p.Arg43*; c.2335C>T, p.Gln779*; c.2863G>T, p.Glu955*); one start loss (c.3G>A).
29574140 Sonoda et al. 2018. The study comprised 151 BrS probands who were symptomatic and/or had a family history of sudden cardiac death, syncope, or arrhythmic diseases. Sanger sequencing identified three frameshift mutations (p.E444fsX14; p.L844RfsX3; p.L1579fsX53) in sup table 3 and three nonsense mutations (p.R1623X; p.W904X; p.W1095X). MLPA analysis identified four large deletions (all exons, exon 4, exon 24, and exons 17-24) in sup table 4.
21288276 Eastaugh et. al. 2011. This is a case report of SCN5A exons 9-10 deletion in a 14 year old boy with Brugada Syndrome by MLPA. Exon 9 and 10 are both out of frame so that the deletion results in mRNA transcript missing these 2 exons, that if translated would code for a protein truncated, suggesting haploinsufficiency. Proband's mom carries the same deletion and has heart defects.
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.
33131149 Pearman et. al. 2020. A total of 561 SCN5A variants associated with BrS were identified, including 12 nonsense and 6 frameshift mutation, listed in supplemental data.

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. This haploinsufficiency score is based on evidence associating loss of function variants with Brugada syndrome specifically. Please note that heterozygous sequence-level variants in SCN5A have been 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 variants; however, these studies have been done in in vitro models and it is unknown whether these variants 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).

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

Triplosensitivity phenotype comment:

Triplosensitivity of SCN5A has not been reported.