KCNH2 Variant A704V

Summary of observed carriers, functional annotations, and structural context for KCNH2 A704V. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

10%

1/11 effective observations

Total carriers

1

0 LQT2 · 1 unaffected

Functional studies

0

Publications with functional data

A704V is present in 1 alleles in gnomAD. This residue resides in a Non_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 103% of WT with a standard error of 7%. 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 (%)
-3.744 0.63 0 0.842 7

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 – 1 1 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 A704V.
Neighbour residue Distance (Å) Observed variants
704 0 A704T, A704V,
703 4
706 5 S706C, S706F,
708 5
700 6
707 6
705 6 W705fsX, W705X,
701 6
702 7
710 8
709 8
762 8
719 9
711 9 I711V,
699 10 E699D, E699D,
764 10
720 10
673 10
686 11
763 11
713 11 M713V,
676 11 Q676fsX, Q676X,
721 11 P721L,
697 11 L697X,
4 11
827 11
712 11 D712N,
761 11
698 12 E698K, E698X,
677 12 M677T,
760 12
672 12 R672C, R672H,
669 13 G669R, G669C, G669X,
767 13 D767X,
724 13 L724X,
765 13
478 13 A478D,
680 13
829 13 D829A, D829E, D829E
696 14 R696C, R696H,
716 14 V716G,
6 14 G6R,
687 14
828 14
682 14 E682X,
714 14
670 14
830 14
479 15
718 15
674 15 H674Y, H674fsX,
481 15
766 15
723 15 C723R, C723G, C723X,
717 15 L717P,
683 15