KCNH2 Variant R176W

Summary of observed carriers, functional annotations, and structural context for KCNH2 R176W. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

10%

46/405 effective observations

Total carriers

395

45 LQT2 · 78 unaffected

Functional studies

3

Publications with functional data

R176W is present in 316 alleles in gnomAD. This residue resides in a Mild_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 20% 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 (%)
-2.776 1.0 -3 0.718 18

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
19160088 2009 112 0 112
24667783 2015 1 0 1
16754261 2006 75 12
29622001 2018 86 0 22
Japan Cohort 2020 1 0 1
Italy Cohort 2020 21 13 8
16818214 2006 1 1
19160088 2009 16 16
France Cohort 2020 1 0 1
24606995 2014 1 0 1
19038855 2009 1 0 1 Seizure
23098067 2012 1 0 1
10862094 2000 6 2 4
14661677 2003 1 1
22067087 2012 1 0 1
22052944 2012 2 1 1
29650123 2018 1 0
22429796 3 0 3
26063740 1 1
Literature, cohort, and gnomAD – 395 78 45 –
Variant features alone – 10 9 1 –

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

Functional data

Functional assay results from published electrophysiology studies. Steady state (S.S.) and peak tail current are relative % to wildtype (100% being no different from wildtype). V1/2 activation and inactivation are the voltages at which half of the maximal current is reached, in mV. Recovery from inactivation and deactivation time are ratios of characteristic time constants with wildtype. HM indicates homomeric channels, HT indicates heteromeric channels.

Homomeric channel data

Published electrophysiology measurements (homomeric).
PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Recov. Inact. Deactivation (%WT)
16754261 CHO 35 15 None None None 0.625
19673885 HEK293 -2.7 -0.9 0.961538462 1.040816327
22052944 hiPSC-CM None None None None

Heteromeric channel data

Published electrophysiology measurements (heteromeric).
PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Deactivation (%WT)
16754261 CHO 100 77 None None 0.5
19673885 HEK293 None None None
22052944 hiPSC-CM 50 None None None

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 R176W.
Neighbour residue Distance (Å) Observed variants
176 0 R176X, R176Q, R176W,
175 4 A175S, A175X, A175D,
177 4 E177X,
174 5
178 5
173 7
179 7 S179W,
172 8 A172V,
180 8
171 8 L171Ins,
181 8 R181Q, R181fsX, R181W,
170 9 L170Ins,
182 9 S182X,
169 10 A169G,
183 10 G183fsX,
168 11
184 11 G184Del,
167 11
185 11
166 12
186 12 G186fsX,
165 13
187 13 G187X, G187S, G187A, G187Del,
164 13 R164C, R164H
188 13 A188S, A188P, A188X,
163 14
189 14 G189Ins,
162 14 T162X,
190 14 A190T, A190V,
161 15
191 15 P191Q, P191fsX,