KCNH2 Variant T613M

Summary of observed carriers, functional annotations, and structural context for KCNH2 T613M. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

71%

90% CI: 69.2% – 86.3%

48/62 effective observations

Total carriers

52

45 LQT2 · 7 unaffected

Functional studies

1

Publications with functional data

T613M has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 0% of WT with a standard error of 0%. 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 3 individuals with LQT2 and 7 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-5.557 1.0 -1 0.945 92

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
24667783 2015 1 0 1
19731233 2009 1 0 in utero demise
15466642 2004 1 0 1
Japan Cohort 2020 9 1 8
Italy Cohort 2020 1 0 1
16379539 2005 2 1 1
20197117 2010 2 0 1
11854117 2002 1 0 1
France Cohort 2020 9 3 6
19038855 2009 2 0 2 Seizure
10220144 1999 1 0 1
10862094 2000 1 0 1
10973849 2000 1 0 1
14720170 2004 1 0 1
14998624 2004 2 0 2
15090700 2004 1 0 1
15840476 2005 6 0 6
16922724 2006 1 0 1
19996378 2009 2 0 2
22402334 2012 1 0 1
24973560 2014 2 1 1
26496715 2015 8 0 8
29766883 2016 3 1 2
29622001 2018 1 0 1
30036649 2018 1 0 1
None 0 1
Literature, cohort, and gnomAD – 52 7 45 –
Variant features alone – 10 7 3 –

Totals may differ from individual publications due to duplicate patients removed during curation.

Functional data

Functional assay results from published electrophysiology studies. Steady state (S.S.) and peak tail current are relative % to wildtype (100% being no different from wildtype). V1/2 activation and inactivation are the voltages at which half of the maximal current is reached, in mV. Recovery from inactivation and deactivation time are ratios of characteristic time constants with wildtype. HM indicates homomeric channels, HT indicates heteromeric channels.

Homomeric channel data

Published electrophysiology measurements (homomeric).
PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Recov. Inact. Deactivation (%WT)
11524404 Xeno 0 None None None None

Heteromeric channel data

Published electrophysiology measurements (heteromeric).
PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Deactivation (%WT)
11524404 Xeno 29 17 2.1 -6.0 None

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 T613M.
Neighbour residue Distance (Å) Observed variants
613 0 T613A, T613L, T613K, T613M,
614 4 A614T, A614V,
612 4 V612L, V612L, V612A,
616 5 Y616S,
609 6 D609N, D609G,
638 6 K638E, K638D, K638Del, K638R,
615 7 L615V, L615F,
630 7 V630I, V630T, V630A,
610 7
617 7 F617L, F617V, F617L, F617L,
611 7 Y611D,
589 7 L589P,
585 7 W585C, W585C,
635 8 N635I,
568 8 W568C, W568C,
565 9
629 9 N629D, N629T, N629S, N629I, N629K, N629K,
586 9 L586M,
632 9 P632A, P632S,
633 9 N633D, N633S, N633I,
618 9 T618S, T618S,
569 10 Y569H, Y569C, Y569X,
608 10
634 10 T634P, T634A, T634S, T634S, T634I,
639 10 I639F, I639N,
592 10 Q592X,
606 10 S606Del, S606P, S606F,
593 10 I593V, I593K, I593T, I593R, I593X,
642 10 I642V, I642Del,
607 10
620 10 S620G, S620I,
631 10 S631F,
605 11 P605L,
588 11 N588D, N588K, N588K,
641 11 S641P, S641F,
619 11
628 11 G628S, G628R, G628Del, G628D, G628A, G628V,
627 11 F627L, F627fsX, F627X, F627L, F627L,
566 11 C566S, C566R, C566G, C566S, C566F,
637 11 E637K, E637G, E637X,
636 11
590 12 G590D, G590V,
431 12 F431L, F431L, F431L,
561 12 A561T, A561P, A561V,
631 12 S631F,
562 12 H562P, H562R, H562Q, H562Q,
564 12 L564L,
572 12 G572S, G572R, G572C, G572D,
621 12 S621R, S621N, S621R, S621R,
632 13 P632A, P632S,
645 13 M645L, M645V, M645L, M645R, M645I, M645I, M645I
584 13 G584S, G584R, G584C,
626 13 G626S, G626A, G626V,
595 13 K595E, K595N, K595N,
637 13 E637K, E637G, E637X,
570 13
567 13 I567T, I567M,
571 13 I571L, I571V,
427 13 Y427H, Y427S, Y427C,
587 14
573 14
591 14 D591N, D591H,
640 14 F640L, F640V, F640Del, F640L, F640L,
640 14 F640L, F640V, F640Del, F640L, F640L,
627 14 F627L, F627fsX, F627X, F627L, F627L,
604 14 G604S, G604C, G604D,
594 14
625 14 V625E,
622 14 L622F,
430 14
641 15 S641P, S641F,
584 15 G584S, G584R, G584C,
633 15 N633D, N633S, N633I,
643 15