KCNH2 Variant S140Y

Summary of observed carriers, functional annotations, and structural context for KCNH2 S140Y. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

7%

0/11 effective observations

Total carriers

1

0 LQT2 · 1 unaffected

Functional studies

0

Publications with functional data

S140Y is present in 1 alleles in gnomAD. This residue resides in a Non_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 138% of WT with a standard error of 15%. In our analysis we used SE < 20% as 'high quality'. Approximately below 50% of WT is considered PS3 moderate and below 30% is PS3 strong.

Variant features alone are equivalent to phenotyping 0 individuals with LQT2 and 10 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-2.069 0.578 -2 0.478 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. BLAST-PSSM reflects evolutionary conservation; more negative values indicate rarer substitutions. Penetrance density summarises neighbouring residue risk (Kroncke et al. 2019).

Reported carrier data

Observed carriers by publication or cohort.
Source Year Carriers Unaffected LQT2 Other Disease
Literature, cohort, and gnomAD – 1 1 0 –
Variant features alone – 10 10 0 –

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

Nearby variants

Neighbouring residues within 15 Ångström provide structural context. Variants listed in the right-most column have been observed clinically or in gnomAD. Note that some residues appear multiple times at different distances since the functional KV11.1 channel (protein product of KCNH2/hERG) is a homotetramer and occasionally the same residue from multiple subunits is present within the 15Å window.

Previously observed variants near S140Y.
Neighbour residue Distance (Å) Observed variants
140 0 S140Y,
139 4 G139R, G139R, G139A,
141 4 P141fsX, P141L, P141S,
138 5
142 5 A142T,
137 7
143 7
136 8
144 8 D144V,
135 8
145 8
134 9 E134X,
146 9 N146X,
133 10 M133T,
147 10 H147R, H147X,
132 11 V132X,
148 11 R148Q, R148fsX, R148W, R148Y,
131 11 V131L, V131L, V131fsX,
149 11 G149V, G149A,
130 12 E130K,
150 12 P150L,
129 13 F129C,
151 13 P151X, P151fsX,
128 13 N128S
152 13 T152I, T152X, T152fsX, T152S, T152S,
127 14
153 14 S153R, S153R, S153R,
126 14
154 14 W154R, W154R, W154X,
125 15
155 15