KCNH2 Variant R164C

Summary of observed carriers, functional annotations, and structural context for KCNH2 R164C. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

9%

0/12 effective observations

Total carriers

2

0 LQT2 · 1 unaffected

Functional studies

1

Publications with functional data

R164C is present in 1 alleles in gnomAD. This residue resides in a Mild_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 74% of WT with a standard error of 6%. 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 (%)
-3.837 1.0 -4 0.903 27

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
24400717 2014 1 0 BrS and SHORT QT
Literature, cohort, and gnomAD – 2 1 0 –
Variant features alone – 10 10 0 –

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)
24400717 CHO 199 172 -3.5 3.1 0.851632047 -1.041218925

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)
24400717 CHO 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 R164C.
Neighbour residue Distance (Å) Observed variants
164 0 R164H, R164C,
163 4
165 4
162 5 T162X,
166 5
161 7
167 7
160 8
168 8
159 8
169 8 A169G,
158 9
170 9 L170Ins,
157 10 P157X,
171 10 L171Ins,
156 11
172 11 A172V,
155 11
173 11
154 12 W154R, W154R, W154X,
174 12
153 13 S153R, S153R, S153R,
175 13 A175S, A175D, A175X,
152 13 T152I, T152X, T152fsX, T152S, T152S,
176 13 R176Q, R176W, R176X,
151 14 P151X, P151fsX,
177 14 E177X,
150 14 P150L,
178 14
149 15 G149V, G149A,
179 15 S179W,