Review of source material: Adler A et al 2020 (PMID: 31983240)
ClinGen: https://search.clinicalgenome.org/kb/genes/HGNC:10593
ClinGen Evidence for Haploinsufficiency: 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).
Literature review:
"...we identified identical intragenic deletions of SCNSA in affected members of two LQT families. This deletion was not identified in more than 500 control individuals. ....SCNSA is the cardiac sodium channel gene. Subtle mutations of this gene would be expected to cause an LQT phenotype. Finally, the type (an in-frame deletion of three amino acids) and location (a region of known importance for sodium channel inactivation) of the deletions support the conclusion that SCN5A is LQT3."
Wang Q et al 1995 PMID: 7889574
"Radical pathogenic variants such as frameshift, nonsense, and splice site types are relatively more frequent in KCNQ1 and KCNH2 and are not present in SCN5A in individuals with LQTS (such pathogenic variants in SCN5A cause Brugada syndrome rather than LQTS)...
SCN5A consists of 28 exons, spans approximately 80 kb; it encodes a protein of 2,016 amino acids (NM_198056.2). An isoform lacking amino acid Gln1077 exists.
More than 200 pathogenic variants are known; they include pathogenic missense variants and in-frame deletions or insertions...
Long QT syndrome (LQTS) associated with biallelic pathogenic variants or heterozygosity for pathogenic variants in two different genes (i.e., digenic pathogenic variants) is generally associated with a more severe phenotype with longer QTc interval and a higher incidence of cardiac events [Schwartz et al 2003, Westenskow et al 2004, Tester et al 2005, Itoh et al 2010]."
Gene reviews LQT https://www.ncbi.nlm.nih.gov/books/NBK1129/
"LQTS3 is caused by gain-of-function mutations of SCN5A. Approximately 8–10% of patients with SCN5A mutations are positively phenotypic as having LQTS. The first SCN5A mutation related to LQT3, the deletion of amino acids 1505–1507 (ΔKPQ), was identified by Wang et al.27 According to previous reports, cardiac events primarily occurred during sleep in LQT3 patients, and 18% died suddenly.28 The gain-of-function SCN5A mutation leads to enhanced INa-P and INa-L, which finally triggers life-threating arrhythmias primarily in LQT3 patients...
The underlying mechanisms of SCN5A mutations that lead to the gain-of-function of INa-P are mainly due to abnormalities in mutation-induced kinetic properties, including augmented INa-P amplitudes, negative shifts in the voltage-dependence of activation, and an increased speed of recovery from inactivation...
An increase in INa-L due to acquired conditions or inherited SCN5A mutations in favor of intracellular Ca2+ loading,47,48 the occurrence of early and delayed after depolarization (EAD and DAD),49,50 triggered activities,51 and spontaneous diastolic depolarization52 that promotes the spatial and temporal dispersion of ventricular repolarization can lead to reentrant arrhythmias...
SCN5A mutations that present with an overlapped phenotype of LQT3 and BrS were also described.124 In vitro studies suggested that these uncommon SCN5A mutations cause a mixed phenotype by altering the amplitude of INa-P and INa-L through enhanced sodium channel inactivation, a negative shift in steady‐state sodium channel inactivation, and enhanced tonic block in response to sodium channel blockers."
Han D et al. 2018 PMID: 29806494
"LQTS3 differs from LQTS1 and LQTS2 in various aspects (5). LQTS3 patients present more often with marked resting bradycardia, and QT interval prolongation is more pronounced during slow heart rate (with in fact normalization at faster heart rates). This behavior may explain why arrhythmic events occur more frequently at rest and are less likely to be triggered by adrenergic stressors (6). Furthermore, the first cardiac event is more likely to be lethal and seems to occur during or after puberty (compared with much earlier in childhood in for example LQTS1)...
Nav1.5 mutations in LQTS3 display a gain-of-function either by a pathological increase in INaL or window current or both...
...Besides a retarded repolarization process, a sustained influx of Na+ ions (through increased INaL) or more Na+ influx (through augmented window current) may lead to higher intracellular Na+ concentrations within the cardiomyocyte. Subsequently, this may cause intracellular Ca2+ overload (through reverse-mode operation of the Na+/Ca2+ exchanger) with potential adverse effects on myocardial contraction, relaxation, and oxygen consumption"
Wilde A et al.2018 PMID: 29798782
"nearly 2% of healthy Caucasians and 5% of healthy nonwhite subjects also host rare missense SCN5A variants"
Kapplinger JD et al 2010 PMID: 20129283
"Although clustering in the three interdomain linkers (IDL), control mutations were scattered throughout all gene regions, highlighting a significantly greater degree of genetic background “noise” in SCN5A than in either KCNQ1 or KCNH2. Moreover, given that the case frequency of missense mutations is lowest in SCN5A, the relative frequency of missense mutations found in cases compared to controls was quite low...
The region in SCN5A with the greatest association between mutation discovery and disease causation was the transmembrane/linker regions..."
Kapa S et al 2009 PMID: 19841300
Inheritance:
Autosomal dominant
(optional) modifiers:
Incomplete penetrance
Digenic (other LQT genes)
Allelic requirement:
Monoallelic_aut
(optional) modifiers:
Digenic (other LQT genes)
Disease associated variant consequences:
Altered gene product structure
Narrative summary of molecular mechanisms:
Mechanism is likely gain of function of SCN5A due to altered gene product structure.
More than 200 pathogenic variants are known, they include pathogenic missense variants and in-frame deletions or insertions. The sodium current mediated by Nav1.5 consists of peak and late components (INa-P and INa-L). It is thought that gain-of-function SCN5A mutations lead to enhanced INa-P and INa-L, which can trigger life-threating arrhythmias.
Rare missense variants are estimated to occur in around 2% of healthy Caucasians and 5% of healthy nonwhite subjects so collectively missense variants are not rare in the healthy population.
Can present with specific features: patients may have marked resting bradycardia, QT interval prolongation more pronounced during slow heart rate (which might explain why arrhythmic events occur more frequently at rest), a first cardiac event that is lethal, and onset after puberty.
Digenic inheritance has been reported with variants in SCN5A reported alongside pathogenic variants in other LQT genes. Biallelic pathogenic variants or digenic pathogenic variants are generally associated with a more severe phenotype with longer QTc interval and a higher incidence of cardiac events.
Note loss of function variants in SCN5A are associated with Brugada syndrome and loss of function and gain of function variants can co-exist causing a mixed phenotype.
List variant classes in this gene proven to cause this disease:
- Missense
- In frame insertion
- In frame deletion
List potential novel variant classes based on predicted functional consequence:
- Splice acceptor variant predicted to escape NMD
- Splice donor variant
- Splice donor variant predicted to escape NMD
- Frameshift predicted to escape NMD
- Stop_gained predicted to escape NMD
- Stop_lost