KCNH2 Variant V549M

Summary of observed carriers, functional annotations, and structural context for KCNH2 V549M. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

11%

90% CI: 0.9% – 28.7%

1/11 effective observations

Total carriers

1

0 LQT2 · 1 unaffected

Functional studies

0

Publications with functional data

V549M 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: 117% of WT with a standard error of 21%. 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 0.995 1 0.823 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 – 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 V549M.
Neighbour residue Distance (Å) Observed variants
549 0 V549M,
548 4
550 5
546 5
547 5 A547T,
552 6 L552S,
543 6 S543fsX,
553 6 L553V,
662 7
551 7 F551L, F551L, F551L,
545 9
659 9
542 9
665 9 R665Q,
658 9
539 9
544 10 E544A, E544fsX,
554 10
555 10
666 10
674 10 H674Y, H674fsX,
661 10 A661V,
663 11
556 11
655 11
540 11 D540fsX,
412 11 W412X,
660 12 S660L,
657 12 G657S, G657V,
415 12
535 12 V535M,
656 12 F656L, F656L, F656L,
541 13 R541C, R541H,
671 13 A671G, A671Del,
670 13
678 13
536 13 A536X,
654 13
667 14 Y667X,
557 14
650 14 L650X,
664 14 Q664X,
675 14
673 14
538 14
681 14 R681W
677 15 M677T,
667 15 Y667X,
419 15