KCNH2 Variant R665Q

Summary of observed carriers, functional annotations, and structural context for KCNH2 R665Q. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

8%

0/13 effective observations

Total carriers

3

0 LQT2 · 1 unaffected

Functional studies

0

Publications with functional data

R665Q is present in 3 alleles in gnomAD. This residue resides in a Non_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 124% of WT with a standard error of 15%. 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 (%)
-3.874 0.97 1 0.821 4

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 – 3 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 R665Q.
Neighbour residue Distance (Å) Observed variants
665 0 R665Q,
662 5
666 6
661 6 A661V,
675 7
546 7
674 7 H674Y, H674fsX,
678 7
668 7 S668L,
664 7 Q664X,
663 8
671 9 A671G, A671Del,
549 9 V549M,
667 9 Y667X,
658 9
547 10 A547T,
659 10
660 10 S660L,
543 10 S543fsX,
550 11
669 11 G669R, G669C, G669X,
677 11 M677T,
679 11 R679W, R679Q,
548 11
673 11
676 11 Q676fsX, Q676X,
682 11 E682X,
670 11
657 11 G657S, G657V,
681 12 R681W,
671 12 A671G, A671Del,
545 12
672 12 R672C, R672H,
544 12 E544A, E544fsX,
664 12 Q664X,
672 12 R672C, R672H,
670 12
553 13 L553V,
669 13 G669R, G669C, G669X,
668 14 S668L,
680 14
654 14
710 14
552 14 L552S,
655 14
709 15
540 15 D540fsX,
711 15 I711V
656 15 F656L, F656L, F656L,
658 15
667 15 Y667X,