KCNH2 Variant S624R Detail

We estimate the penetrance of LQTS for KCNH2 S624R is 33%. This variant was found in a total of 1 carriers in 1 papers or gnomAD (version 4), 1 had LQTS. S624R is not present in gnomAD. We have tested the trafficking efficiency of this variant, 85% of WT with a standard error of 19%; 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. S624R 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 2 individuals with LQT2 and 8 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 S624R around 33% (3/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.876 0.999 -1 0.955 74
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
29766883 2016 1 0 1
LITERATURE, COHORT, AND GNOMAD: - 1 0 1 -
VARIANT FEATURES ALONE: - 10 8 2 -
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.

S624R has 96 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
624 0 S624R, S624R, S624R, S624N,
625 4 V625E,
623 4 T623I,
625 5 V625E,
624 5 S624R, S624R, S624R, S624N,
624 5 S624R, S624R, S624R, S624N,
621 6 S621R, S621R, S621R, S621N,
620 6 S620I, S620G,
626 7 G626S, G626A, G626V,
623 7 T623I,
624 7 S624R, S624R, S624R, S624N,
622 7 L622F,
652 7 Y652X,
625 8 V625E,
626 8 G626S, G626A, G626V,
625 8 V625E,
645 8 M645I, M645L, M645V, M645I, M645L, M645I, M645R,
626 9 G626S, G626A, G626V,
645 9 M645I, M645L, M645V, M645I, M645L, M645I, M645R,
648 9 G648A,
620 9 S620I, S620G,
623 9 T623I,
627 9 F627X, F627fsX, F627L, F627L, F627L,
649 9
621 9 S621R, S621R, S621R, S621N,
627 9 F627X, F627fsX, F627L, F627L, F627L,
626 9 G626S, G626A, G626V,
649 10
652 10 Y652X,
619 10
652 10 Y652X,
644 10 V644I, V644F,
620 10 S620I, S620G,
623 10 T623I,
621 10 S621R, S621R, S621R, S621N,
648 11 G648A,
618 11 T618S, T618S,
622 11 L622F,
622 11 L622F,
617 11 F617L, F617V, F617L, F617L,
641 12 S641P, S641F,
653 12
652 12 Y652X,
627 12 F627X, F627fsX, F627L, F627L, F627L,
656 12 F656L, F656L, F656L,
619 12
627 12 F627X, F627fsX, F627L, F627L, F627L,
616 12 Y616S,
620 12 S620I, S620G,
557 12
651 12 M651K,
647 12
644 12 V644I, V644F,
646 12
641 12 S641P, S641F,
646 12
621 13 S621R, S621R, S621R, S621N,
628 13 G628A, G628Del, G628S, G628R, G628V, G628D,
642 13 I642V, I642Del,
648 13 G648A,
653 13
650 13 L650X,
645 13 M645I, M645L, M645V, M645I, M645L, M645I, M645R,
642 13 I642V, I642Del,
656 13 F656L, F656L, F656L,
645 13 M645I, M645L, M645V, M645I, M645L, M645I, M645R,
649 13
616 13 Y616S,
628 14 G628A, G628Del, G628S, G628R, G628V, G628D,
649 14
622 14 L622F,
630 14 V630T, V630I, V630A,
561 14 A561T, A561P, A561V,
647 14
650 14 L650X,
643 14
618 14 T618S, T618S,
628 14 G628A, G628Del, G628S, G628R, G628V, G628D,
617 14 F617L, F617V, F617L, F617L,
617 14 F617L, F617V, F617L, F617L,
653 14
655 14
615 14 L615F, L615V,
648 14 G648A,
631 14 S631F,
618 15 T618S, T618S,
619 15
557 15
640 15 F640Del, F640L, F640V, F640L, F640L,
564 15 L564L,
560 15 I560fsX, I560M,
632 15 P632S, P632A,
629 15 N629D, N629K, N629K, N629T, N629S, N629I,
628 15 G628A, G628Del, G628S, G628R, G628V, G628D,
651 15 M651K,
654 15