SCN5A Variant L227P

Summary of observed carriers, functional annotations, and structural context for SCN5A L227P. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

3%

0/14 effective observations

Estimated BrS1 penetrance

22%

3/14 effective observations

Total carriers

4

1 BrS1 · 0 LQT3 · 3 unaffected

L227P is present in 3 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 2 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 (%)
-6.83 0.999 -6.99 0.925 18 6

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
28127136 2017 1 0 1 0
30059973 2018 1 1 0 0
Literature, cohort, and gnomAD – 4 3 0 1 –
Variant features alone – 15 13 0 2 – –

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). V1/2 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) V1/2 Activation (mV) V1/2 Inactivation (mV) Late/Persistent Current (% WT)
28127136 2017
30059973 2018

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 L227P.
Neighbour residue Distance (Å) Observed variants
848 7 I848F,
223 8 V223L,
856 12 V856L, V856L,
842 15
240 10 V240M,
231 9 c.692_693delCA,
198 14
193 7 W193R, W193R, W193X,
195 12
926 15
237 14
228 6 K228R,
138 11 M138I, M138I, M138I,
925 12 I925F,
227 0 L227P,
137 14 I137V,
142 12
197 10
229 6
851 10 c.2550_2551dupGT, F851L, p.F851CfsX19, c.2552_2553dupGT, F851L, F851L,
221 12
196 7
852 7
854 13 c.2559delT,
222 13 R222X, R222Q, R222L,
224 6 L224F,
845 9 c.2533delG,
232 11 V232I, V232F,
244 13
191 13
849 8
226 4 A226G, A226V,
921 15
241 14
843 15 T843A,
930 15 c.2787+17_2787+18insACACACACACACACACACACACA, c.2788-6C>T
144 12
855 12
239 13 I239V, I239V ,
230 6 I230V, I230T, I230M,
199 12 S199T,
139 15 p.I137_C139dup,
148 13
841 14 p.N841TfsX2, N841K, N841K,
236 12
847 11
203 14
846 12 L846R,
192 11
168 14
233 11
194 12
141 10 I141V, I141N,
853 11
201 14
225 7 R225W, R225Q,
844 12 L844RfsX3,
850 12 V850M, c.2549_2550insTG,
243 12
200 10
145 11
140 14
220 14 T220I,