SCN5A Variant Y1228H

Summary of observed carriers, functional annotations, and structural context for SCN5A Y1228H. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

7%

0/12 effective observations

Estimated BrS1 penetrance

23%

2/12 effective observations

Total carriers

2

1 BrS1 · 0 LQT3 · 1 unaffected

Y1228H is present in 1 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 (%)
-4.52 0.571 4.12 0.854 20 2

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
16643399 2006 1 0 1 0
20129283 2010 1 0 1 0
Literature, cohort, and gnomAD – 2 1 0 1 –
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). 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)
16643399 2006
20129283 2010

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 Y1228H.
Neighbour residue Distance (Å) Observed variants
1233 12 K1233E,
387 14
330 13 S330F,
1234 12
1698 10 A1698T,
1220 14 G1220E,
1673 14
1681 11 c.5040_5042delTTAinsC, Y1681F,
1694 13
1226 7
1695 8 Q1695X,
1221 13 A1221V,
1676 11 M1676T, M1676I, M1676I, M1676I,
1672 14 S1672Y,
1693 11
1699 11
1239 13 L1239P,
331 11
1680 12 A1680T, A1680P,
1235 9
1231 6 E1231K,
1701 15 M1701I, M1701I, M1701I
1228 0 Y1228H, Y1228C, Y1228F,
1690 13 c.5068_5070delGA, D1690N,
1223 10 c.3667delG,
1697 9
1227 5
1222 13 p.L1222LfsX7, L1222R,
1230 9 E1230K,
1229 7
1696 7
1700 13
1677 14
1224 8
1225 9 E1225K, G1225K,
1691 14
1232 10 R1232W, R1232Q,
1238 15
1236 12 K1236R, K1236N, K1236N,