KCNH2 Variant A548S

Summary of observed carriers, functional annotations, and structural context for KCNH2 A548S. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

11%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

A548S has not been reported in gnomAD. This residue resides in a Non_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 77% of WT with a standard error of 17%. 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 (%)
-2.875 0.859 1 0.775 8

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 – 0 0 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 A548S.
Neighbour residue Distance (Å) Observed variants
548 0
547 4 A547T,
549 4 V549M,
546 5
551 6 F551L, F551L, F551L,
550 6
545 6
552 6 L552S,
543 7 S543fsX,
542 8
412 9 W412X,
544 9 E544A, E544fsX,
553 9 L553V,
662 10
555 10
666 11
554 11
415 11
539 11
665 11 R665Q,
659 11
540 11 D540fsX,
541 12 R541C, R541H,
556 12
663 12
674 12 H674Y, H674fsX,
535 13 V535M,
658 13
416 13
411 13
661 13 A661V,
655 14
408 14
419 14
678 14
667 14 Y667X,
409 14 V409M, V409L, V409L,
681 14 R681W
538 14
536 15 A536X,
660 15 S660L,
3 15
413 15 L413P,
650 15 L650X,
414 15 I414fsX,