KCNH2 Variant A547T

Summary of observed carriers, functional annotations, and structural context for KCNH2 A547T. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

6%

90% CI: 0.6% – 24.9%

1/18 effective observations

Total carriers

8

0 LQT2 · 2 unaffected

Functional studies

0

Publications with functional data

A547T is present in 8 alleles in gnomAD. This residue resides in a Non_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 114% of WT with a standard error of 20%. 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 (%)
-3.834 0.976 0 0.868 3

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 – 8 2 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 A547T.
Neighbour residue Distance (Å) Observed variants
547 0 A547T,
546 3
548 4
550 5
549 5 V549M,
545 7
666 7
551 8 F551L, F551L, F551L,
662 8
552 9 L552S,
543 9 S543fsX,
663 10
665 10 R665Q,
553 10 L553V,
544 10 E544A, E544fsX,
659 10
667 11 Y667X,
554 11
542 11
412 12 W412X,
661 12 A661V,
555 12
674 13 H674Y, H674fsX,
678 13
658 13
660 13 S660L,
650 14 L650X,
664 14 Q664X,
681 14 R681W
539 14
668 14 S668L,
540 14 D540fsX,
415 14
556 14
541 14 R541C, R541H,
655 14
656 15 F656L, F656L, F656L,
654 15