SCN5A Variant A166T

Summary of observed carriers, functional annotations, and structural context for SCN5A A166T. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

0/80 effective observations

Estimated BrS1 penetrance

1/80 effective observations

Total carriers

0 BrS1 · 0 LQT3 · 70 unaffected

A166T is present in 70 alleles in gnomAD. This residue resides in a Mild_Hotspot region for Brugada syndrome and a Non_Hotspot region for LQT3.

Variant features alone are equivalent to phenotyping 1 individuals for Brugada syndrome and 0 individuals for LQT3.

In silico predictors

Variant-level computational predictors.
PROVEAN	PolyPhen-2	BLAST-PSSM	REVEL	Penetrance Density BrS (%)	Penetrance Density LQT3 (%)
-2.26	0.999	-0.59	0.801	11	0

PROVEAN scores below -2 suggest deleterious impact. REVEL scores above 0.5–0.75 are often interpreted as likely pathogenic. PolyPhen-2 scores above 0.85 are typically pathogenic. Penetrance density summarises neighbouring residue risk (Kroncke et al. 2019).

Reported carrier data

Observed carriers by publication or cohort.
Source	Year	Carriers	Unaffected	LQT3	BrS1	Other	Other Disease
Literature, cohort, and gnomAD	–	70	70	0	0		–
Variant features alone	–	15	14	0	1	–	–

Totals may differ from individual publications due to duplicate patients removed during curation.

Functional data

Peak and late/persistent current values are relative to wild-type (100% indicates no change). V_1/2 activation and inactivation denote the membrane potentials (mV) at which half-maximal current is achieved.

Published electrophysiology measurements.
PubMed ID	Year	Cell Type	Peak Current (% WT)	V_1/2 Activation (mV)	V_1/2 Inactivation (mV)	Late/Persistent Current (% WT)
32533946	2020	HEK	103	4.2	-8.5

Nearby variants

Neighbouring residues within 15 Ångström provide structural context. Variants listed in the right-most column have been observed clinically or in gnomAD.

Previously observed variants near A166T.
Neighbour residue	Distance (Å)	Observed variants
198	14
147	15
164	7	F164L, F164L, F164L,
209	15	N209S, N209T,
170	7	F170I,
171	9
143	14
137	11	I137V,
158	14	K158T,
197	14
163	5	c.486delC,
169	5
222	13	R222X, R222Q, R222L,
174	12	V174I,
133	13
157	15	T157I,
160	10	p.V160fs,
205	10	c.612-2A>G, Y205X,
206	14
166	0	A166T,
144	13
172	10
139	15	p.I137_C139dup,
165	4
204	10	A204T, c.611+1G>A, c.611+3_611+4dupAA, A204V,
162	8	Y162H, Y162C,
208	10	E208K,
136	13	L136P,
168	6
202	13	I202T,
175	14	K175N, K175N,
141	13	I141V, I141N,
167	4
161	10	E161K, E161Q,
201	10
225	13	R225W, R225Q
159	12	Y159C, Y159X,
207	14
173	11
200	14
140	10