KCNH2 Variant S641P Detail

We estimate the penetrance of LQTS for KCNH2 S641P is 80%. This variant was found in a total of 1 carriers in 1 papers or gnomAD, 1 had LQTS. S641P is not present in gnomAD. S641P 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 7 individuals with LQT2 and 3 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 S641P around 80% (8/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.734 0.228 -1 0.904 85
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
Japan Cohort 2020 1 0 1
LITERATURE, COHORT, AND GNOMAD: - 1 0 1 -
VARIANT FEATURES ALONE: - 10 3 7 -
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.

S641P has 76 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
641 0 S641P, S641F,
642 4 I642V, I642Del,
640 5 F640L, F640L, F640V, F640Del, F640L,
645 5 M645I, M645R, M645I, M645L, M645L, M645V, M645I,
644 5 V644I, V644F,
616 6 Y616S,
643 6
638 6 K638R, K638Del, K638E, K638D,
639 6 I639F, I639N,
621 7 S621R, S621R, S621R, S621N,
632 7 P632S, P632A,
627 7 F627L, F627fsX, F627L, F627X, F627L,
637 8 E637G, E637X, E637K,
617 8 F617V, F617L, F617L, F617L,
619 8
620 9 S620G, S620I,
568 9 W568C, W568C,
646 9
618 9 T618S, T618S,
636 9
625 9 V625E,
631 9 S631F,
615 10 L615F, L615V,
622 10 L622F,
564 10 L564L,
620 10 S620G, S620I,
647 10
612 10 V612A, V612L, V612L,
623 10 T623I,
648 10 G648A,
634 10 T634A, T634S, T634S, T634P, T634I,
626 10 G626S, G626A, G626V,
613 11 T613L, T613M, T613A, T613K,
635 11 N635I,
629 11 N629T, N629K, N629D, N629S, N629K, N629I,
630 11 V630A, V630I, V630T,
633 11 N633I, N633D, N633S,
626 11 G626S, G626A, G626V,
571 11 I571L, I571V,
617 11 F617V, F617L, F617L, F617L,
567 11 I567T, I567M,
618 12 T618S, T618S,
624 12 S624R, S624R, S624N, S624R,
649 12
614 12 A614T, A614V,
630 12 V630A, V630I, V630T,
585 12 W585C, W585C,
628 12 G628R, G628Del, G628S, G628V, G628D, G628A,
565 12
621 12 S621R, S621R, S621R, S621N,
614 12 A614T, A614V,
624 12 S624R, S624R, S624N, S624R,
623 12 T623I,
625 13 V625E,
622 13 L622F,
561 13 A561V, A561T, A561P,
628 13 G628R, G628Del, G628S, G628V, G628D, G628A,
619 13
611 14 Y611D,
561 14 A561V, A561T, A561P,
616 14 Y616S,
557 14
609 14 D609G, D609N,
627 14 F627L, F627fsX, F627L, F627X, F627L,
558 14 A558E, A558V, A558P,
615 14 L615F, L615V,
584 14 G584R, G584C, G584S,
570 14
560 14 I560fsX, I560M,
572 14 G572C, G572S, G572D, G572R,
650 14 L650X,
613 15 T613L, T613M, T613A, T613K,
625 15 V625E,
566 15 C566S, C566F, C566G, C566R, C566S,
651 15 M651K,
565 15