KCNH2 Variant R181W

Summary of observed carriers, functional annotations, and structural context for KCNH2 R181W. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

14%

2/15 effective observations

Total carriers

5

1 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

R181W is present in 4 alleles in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 69% of WT with a standard error of 18%. 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 1 individuals with LQT2 and 9 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-1.838 1.0 -3 0.583 46

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
21216356 2011 1 0 1
Literature, cohort, and gnomAD – 5 0 1 –
Variant features alone – 10 9 1 –

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 R181W.
Neighbour residue Distance (Å) Observed variants
181 0 R181Q, R181fsX, R181W,
180 4
182 4 S182X,
179 5 S179W,
183 5 G183fsX,
178 7
184 7 G184Del,
177 8 E177X,
185 8
176 8 R176X, R176Q, R176W,
186 8 G186fsX,
175 9 A175S, A175X, A175D,
187 9 G187X, G187S, G187A, G187Del,
174 10
188 10 A188S, A188P, A188X,
173 11
189 11 G189Ins,
172 11 A172V,
190 11 A190T, A190V,
171 12 L171Ins,
191 12 P191Q, P191fsX,
170 13 L170Ins,
192 13 G192fsX,
169 13 A169G,
193 13 A193fsX, A193V, A193X, A193T,
168 14
194 14 V194M,
167 14
195 14
166 15
196 15