KCNH2 Variant A175D

Summary of observed carriers, functional annotations, and structural context for KCNH2 A175D. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

2%

0/41 effective observations

Total carriers

31

0 LQT2 · 9 unaffected

Functional studies

0

Publications with functional data

A175D is present in 31 alleles in gnomAD. This residue resides in a Mild_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 80% of WT with a standard error of 21%. 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 (%)
-1.033 0.01 -1 0.4 10

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 – 31 9 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 A175D.
Neighbour residue Distance (Å) Observed variants
175 0 A175S, A175D, A175X,
174 4
176 4 R176Q, R176W, R176X,
173 5
177 5 E177X,
172 7 A172V,
178 7
171 8 L171Ins,
179 8 S179W,
170 8 L170Ins,
180 8
169 9 A169G,
181 9 R181fsX, R181Q, R181W,
168 10
182 10 S182X,
167 11
183 11 G183fsX,
166 11
184 11 G184Del,
165 12
185 12
164 13 R164H, R164C,
186 13 G186fsX,
163 13
187 13 G187Del, G187S, G187A, G187X,
162 14 T162X,
188 14 A188S, A188X, A188P,
161 14
189 14 G189Ins,
160 15
190 15 A190V, A190T,