Table 2.

Simplified Framework for Functional Effect, Location, and Phenotype of Variants in Sodium Channelopathies^*

	SCN1A	SCN2A	SCN4A	SCN5A	SCN8A	SCN9A
Predominant Location of gene	Central nervous system	Central nervous system	Muscle	Heart	Central nervous system	Dorsal Root Ganglion
LOSS OF FUNCTION
Type of variant	Nonsense and Frameshift more than missense	Nonsense and Frameshift more than missense	Few reports in literature	Missense more than Nonsense	Missense more than Frameshift	Nonsense more than missense
Common location of Missense variants	P > VSR	P	Few reports in literature	Distributed throughout TM	P	P (S5–6)
Prototypic phenotype	EOEE	ASD, DD with or without later onset seizures	Normal (het) Congenital Myopathy (hom / biallelic)	Brugada Syndrome	DD, ataxia	Normal (het) Congenital indifference to pain (hom / biallelic)
GAIN OF FUNCTION**
Type of variant	Missense	Missense	Missense	Missense	Missense	Missense
Common location of missense variants	VSR	VSR; sparing of S5–6	VSR > P with sparing of S5–6 and S6	DIII–DIV linker, VSR, S6	VSR; sparing of S5–6	DIII–DIV linker, VSR > P with sparing of S5–6
Prototypic phenotype	EOEE > GEFS+	EOEE> B(F)NIS	Paroxysmal neuromuscular disorders	Prolonged QT Syndrome 3	EOEE	Paroxysmal pain disorders

^*There is considerable molecular and clinical heterogeneity of the variants. The table lists the most frequent associations but this is not exclusive. This has been compiled from multiple sources^{5, 19, 26, 27, 29–32};

^**Many missense variants in VSR have complicated functional effects with mixed electrophysiological changes but most exhibit some gain of function properties.

Abbreviations: As in Table 1, in addition, DD = Developmental delay; ASD= Autism spectrum disorders; P = pore (S5, S5–6, S6); VSR= voltage sensor region (S3–4, S4; S4–5); TMO= transmembrane; het= heterozygous, hom=homozygous.