KCNH2 Variant M554I

Summary of observed carriers, functional annotations, and structural context for KCNH2 M554I. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

13%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

M554I has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 94% of WT with a standard error of 11%. 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 0.616 1 0.902 44

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 M554I.
Neighbour residue Distance (Å) Observed variants
554 0
553 6 L553V,
555 6
557 6
550 6
556 7
551 7 F551L, F551L, F551L,
646 7
650 7 L650X,
558 7 A558P, A558E, A558V,
656 7 F656L, F656L, F656L,
552 8 L552S,
655 8
659 8
649 8
549 10 V549M,
647 10
559 10 L559F, L559H,
560 10 I560fsX, I560M,
548 11
648 11 G648A,
619 11
651 11 M651K,
652 11 Y652X,
658 11
547 11 A547T,
662 12
561 12 A561T, A561P, A561V,
653 12
660 12 S660L,
657 12 G657S, G657V,
643 12
645 12 M645L, M645V, M645L, M645R, M645I, M645I, M645I,
663 12
623 12 T623I,
651 12 M651K,
622 12 L622F,
654 12
654 12
642 12 I642V, I642Del,
419 13
546 13
653 13
644 13 V644I, V644F,
661 13 A661V
562 14 H562P, H562R, H562Q, H562Q,
648 14 G648A,
615 14 L615V, L615F,
415 14
563 15 W563G, W563C, W563C, W563X,
618 15 T618S, T618S,
652 15 Y652X,