KCNH2 Variant H674Y

Summary of observed carriers, functional annotations, and structural context for KCNH2 H674Y. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

10%

90% CI: 0.8% – 28.0%

1/11 effective observations

Total carriers

1

0 LQT2 · 1 unaffected

Functional studies

0

Publications with functional data

H674Y 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: 118% of WT with a standard error of 13%. 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 (%)
-5.813 0.997 2 0.91 9

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 H674Y.
Neighbour residue Distance (Å) Observed variants
674 0 H674Y, H674fsX,
673 4
675 6
671 6 A671G, A671Del,
670 6
677 6 M677T,
543 7 S543fsX,
678 7
665 7 R665Q,
669 8 G669R, G669C, G669X,
676 8 Q676fsX, Q676X,
672 8 R672C, R672H,
544 9 E544A, E544fsX,
681 9 R681W,
540 9 D540fsX,
546 10
705 10 W705fsX, W705X,
549 10 V549M,
662 10
668 10 S668L,
701 11
679 11 R679W, R679Q,
539 11
702 11
680 11
545 12
667 12 Y667X,
661 12 A661V,
3 12
658 12
710 12
666 12
664 12 Q664X,
548 12
682 13 E682X,
547 13 A547T,
542 13
698 13 E698K, E698X,
668 13 S668L,
4 14
541 14 R541C, R541H,
706 14 S706C, S706F
709 14
550 14
664 14 Q664X,
553 14 L553V,
659 14
663 15
552 15 L552S,
704 15 A704T, A704V,
666 15