KCNH2 Variant M677T

Summary of observed carriers, functional annotations, and structural context for KCNH2 M677T. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

11%

90% CI: 0.9% – 28.5%

1/11 effective observations

Total carriers

1

0 LQT2 · 1 unaffected

Functional studies

0

Publications with functional data

M677T is present in 1 alleles in gnomAD. This residue resides in a Non_Hotspot region for LQT2.

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 (%)
-5.832 0.981 -1 0.911 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 – 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 M677T.
Neighbour residue Distance (Å) Observed variants
677 0 M677T,
681 5 R681W,
678 5
680 5
673 6
676 6 Q676fsX, Q676X,
674 6 H674Y, H674fsX,
701 6
675 7
679 8 R679W, R679Q,
698 8 E698K, E698X,
702 8
544 9 E544A, E544fsX,
682 9 E682X,
705 10 W705fsX, W705X,
697 10 L697X,
684 10
543 11 S543fsX,
671 11 A671G, A671Del,
672 11 R672C, R672H,
683 11
3 11
665 11 R665Q,
670 11
694 11 R694C, R694H,
716 11 V716G,
540 12 D540fsX,
685 12 R685C, R685H, R685P,
669 12 G669R, G669C, G669X,
4 12
704 12 A704T, A704V,
545 12
700 12
720 12
699 12 E699D, E699D,
546 12
710 12
706 13 S706C, S706F,
719 13
711 13 I711V,
5 14
703 14
689 14
715 14 A715T, A715A, A715V, A715sp,
541 14 R541C, R541H,
695 14
666 14
668 14 S668L,
668 15 S668L,
549 15 V549M,
539 15
708 15
709 15
717 15 L717P
662 15
712 15 D712N,
693 15 L693X,