KCNH2 Variant A661V

Summary of observed carriers, functional annotations, and structural context for KCNH2 A661V. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

9%

90% CI: 0.5% – 25.4%

0/11 effective observations

Total carriers

1

0 LQT2 · 1 unaffected

Functional studies

0

Publications with functional data

A661V 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: 125% of WT with a standard error of 3%. 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 (%)
-3.876 0.999 0 0.941 13

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 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 A661V.
Neighbour residue Distance (Å) Observed variants
661 0 A661V,
662 4
660 4 S660L,
664 5 Q664X,
663 6
659 6
658 6
657 6 G657S, G657V,
665 6 R665Q,
666 9
654 9
664 10 Q664X,
668 10 S668L,
657 10 G657S, G657V,
656 10 F656L, F656L, F656L,
550 10
653 10
667 10 Y667X,
671 10 A671G, A671Del,
549 10 V549M,
655 11
546 11
658 11
654 11
553 11 L553V,
675 11
660 12 S660L,
674 12 H674Y, H674fsX
671 12 A671G, A671Del,
547 12 A547T,
650 12 L650X,
653 12
661 13 A661V,
661 13 A661V,
663 13
669 13 G669R, G669C, G669X,
678 13
670 13
670 13
548 13
655 13
554 13
660 14 S660L,
543 14 S543fsX,
672 14 R672C, R672H,
668 14 S668L,
652 14 Y652X,
657 14 G657S, G657V,
672 14 R672C, R672H,
649 14
667 14 Y667X,
651 15 M651K,
552 15 L552S,
656 15 F656L, F656L, F656L,
659 15
669 15 G669R, G669C, G669X,