KCNH2 Variant V194M

Summary of observed carriers, functional annotations, and structural context for KCNH2 V194M. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

6%

1/25 effective observations

Total carriers

15

0 LQT2 · 2 unaffected

Functional studies

0

Publications with functional data

V194M is present in 14 alleles in gnomAD. This residue resides in a Mild_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 0% 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 (%)
-0.971 0.999 1 0.497 20

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
Italy Cohort 2020 1 1 0
Literature, cohort, and gnomAD – 15 2 0 –
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 V194M.
Neighbour residue Distance (Å) Observed variants
194 0 V194M,
193 4 A193V, A193X, A193fsX, A193T
195 4
192 5 G192fsX,
196 5
191 7 P191fsX, P191Q,
197 7 D197N, D197Y,
190 8 A190V, A190T,
198 8 V198L, V198L,
189 8 G189Ins,
199 8
188 9 A188S, A188X, A188P,
200 9 L200Q,
187 10 G187Del, G187S, G187A, G187X,
201 10
186 11 G186fsX,
202 11
185 11
203 11 A203T,
184 12 G184Del,
204 12
183 13 G183fsX,
205 13 P205L,
182 13 S182X,
206 13
181 14 R181fsX, R181Q, R181W,
207 14 S207X,
180 14
208 14 E208X,
179 15 S179W,
209 15