KCNH2 Variant K608M Detail

We estimate the penetrance of LQTS for KCNH2 K608M is 81%. We are unaware of any observations of this variant in individuals. K608M is not present in gnomAD. K608M has not been functionally characterized. This residue is located in a Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 8 individuals with LQT2 and 2 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 K608M around 81% (8/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.766 0.983 -2 0.905 87
PROVEAN scores less than -2 are considered deleterious. REVEL scores higher than 0.5 or 0.75 are considered likely pathogenic (higher sensitivity with the former cutoff, higher specificity with the latter cutoff). A PolyPhen-2 score of 0.85 or greater is considered likely pathogenic. BLAST-PSSM reflects the evolutionary conservation of residue substitutions, more negative numbers indicate fewer observations of the specific substitution than is expected. Penetrance density is our previously published method to calculate the average LQTS probability density in a shell of residues surrounding a residue of interest (Kroncke et al. 2019).

Reported Carrier Data

PubMed ID Year Carriers Unaffected LQT2 Other Disease
LITERATURE, COHORT, AND GNOMAD: - 0 0 0 -
VARIANT FEATURES ALONE: - 10 2 8 -
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts. We do not distinguish here between multiple missense codons. Missense variants are combined across degenerate codon substitutions since codon-level data were not consistently available for curation.

K608M has 39 previously observed neighbors within 15 angstroms

A residue within a folded protein on average has nearest neighbors that fall roughly into two shells: a "nearest" neighbor around 5-6 angstroms and a second shell around 11 angstroms. NOTE: 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 15A window. All variants shown in the rightmost column have been observed in at least one individual in the literature or gnomAD.

Neighbor Distance (Angstroms) Variants Observed in Individuals
608 0
609 5 D609G, D609N,
607 6
606 6 S606P, S606F, S606Del,
635 6 N635I,
612 6 V612A, V612L, V612L,
611 7 Y611D,
610 8
639 10 I639F, I639N,
613 10 T613L, T613M, T613A, T613K,
636 10
427 10 Y427H, Y427C, Y427S,
605 10 P605L,
638 10 K638R, K638Del, K638E, K638D,
431 11 F431L, F431L, F431L,
634 11 T634A, T634S, T634S, T634P, T634I,
614 11 A614T, A614V,
615 11 L615F, L615V,
593 12 I593V, I593K, I593X, I593T, I593R,
569 13 Y569H, Y569C, Y569X,
595 13 K595N, K595N, K595E,
604 13 G604S, G604D, G604C,
589 13 L589P,
637 13 E637G, E637X, E637K,
616 13 Y616S,
565 13
642 13 I642V, I642Del,
562 13 H562R, H562Q, H562Q, H562P,
633 14 N633I, N633D, N633S,
566 14 C566S, C566F, C566G, C566R, C566S,
424 14
575 14 E575K,
432 14
586 14 L586M,
430 14
428 14 S428X, S428L, S428fsX,
594 15
632 15 P632S, P632A,
423 15