KCNH2 Variant V630A Detail

We estimate the penetrance of LQTS for KCNH2 V630A is 45%. This variant was found in a total of 2 carriers in 3 papers or gnomAD (version 4), 2 had LQTS. V630A is not present in gnomAD. We have tested the trafficking efficiency of this variant, 0% of WT with a standard error of 5%; 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. V630A 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 3 individuals with LQT2 and 7 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 V630A around 45% (5/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.867 0.985 0 0.966 83
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
11854117 2002 1 0 1
9693036 1998 1 0 1
15840476 2005 1 0 1
LITERATURE, COHORT, AND GNOMAD: - 2 0 2 -
VARIANT FEATURES ALONE: - 10 7 3 -
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.

V630A has 82 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
630 0 V630I, V630A, V630T,
631 4 S631F,
629 5 N629S, N629T, N629D, N629K, N629I, N629K,
628 5 G628R, G628A, G628S, G628Del, G628D, G628V,
617 6 F617V, F617L, F617L, F617L,
616 7 Y616S,
613 7 T613A, T613K, T613M, T613L,
585 7 W585C, W585C,
632 7 P632S, P632A,
588 8 N588D, N588K, N588K,
627 8 F627L, F627L, F627X, F627L, F627fsX,
627 8 F627L, F627L, F627X, F627L, F627fsX,
614 8 A614T, A614V,
589 8 L589P,
626 8 G626A, G626V, G626S,
568 8 W568C, W568C,
620 9 S620I, S620G,
592 9 Q592X,
629 9 N629S, N629T, N629D, N629K, N629I, N629K,
632 9 P632S, P632A,
638 9 K638D, K638E, K638R, K638Del,
628 9 G628R, G628A, G628S, G628Del, G628D, G628V,
633 9 N633I, N633D, N633S,
633 10 N633I, N633D, N633S,
631 10 S631F,
637 10 E637K, E637G, E637X,
621 10 S621R, S621R, S621N, S621R,
618 10 T618S, T618S,
584 10 G584C, G584R, G584S,
586 10 L586M,
641 11 S641F, S641P,
615 11 L615F, L615V,
612 11 V612L, V612A, V612L,
626 11 G626A, G626V, G626S,
628 11 G628R, G628A, G628S, G628Del, G628D, G628V,
625 11 V625E,
638 12 K638D, K638E, K638R, K638Del,
593 12 I593R, I593X, I593K, I593T, I593V,
590 12 G590D, G590V,
625 12 V625E,
565 12
626 12 G626A, G626V, G626S,
640 12 F640V, F640L, F640L, F640Del, F640L,
609 12 D609N, D609G,
641 12 S641F, S641P,
634 12 T634S, T634P, T634I, T634S, T634A,
616 12 Y616S,
591 12 D591N, D591H,
610 12
619 12
587 13
634 13 T634S, T634P, T634I, T634S, T634A,
642 13 I642V, I642Del,
630 13 V630I, V630A, V630T,
630 13 V630I, V630A, V630T,
572 13 G572R, G572C, G572D, G572S,
571 13 I571V, I571L,
592 13 Q592X,
569 13 Y569H, Y569C, Y569X,
645 13 M645V, M645L, M645I, M645I, M645R, M645L, M645I,
637 13 E637K, E637G, E637X,
635 13 N635I,
644 13 V644I, V644F,
583 14 I583V,
611 14 Y611D,
628 14 G628R, G628A, G628S, G628Del, G628D, G628V,
622 14 L622F,
564 14 L564L,
624 14 S624R, S624N, S624R, S624R,
645 14 M645V, M645L, M645I, M645I, M645R, M645L, M645I,
623 14 T623I,
636 14
620 14 S620I, S620G,
626 14 G626A, G626V, G626S,
629 14 N629S, N629T, N629D, N629K, N629I, N629K,
639 15 I639N, I639F,
621 15 S621R, S621R, S621N, S621R,
605 15 P605L,
561 15 A561P, A561T, A561V,
627 15 F627L, F627L, F627X, F627L, F627fsX,
567 15 I567M, I567T,
627 15 F627L, F627L, F627X, F627L, F627fsX,