KCNH2 Variant V625L Detail

We estimate the penetrance of LQTS for KCNH2 V625L is 75%. We are unaware of any observations of this variant in individuals. V625L is not present in gnomAD. V625L 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 V625L around 75% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.9 0.989 1 0.925 86
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 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.

V625L has 85 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
625 0 V625E,
626 4 G626V, G626A, G626S,
624 4 S624R, S624N, S624R, S624R,
624 5 S624R, S624N, S624R, S624R,
620 5 S620G, S620I,
626 5 G626V, G626A, G626S,
627 5 F627L, F627L, F627fsX, F627X, F627L,
623 6 T623I,
625 6 V625E,
625 6 V625E,
621 6 S621R, S621R, S621R, S621N,
645 7 M645L, M645I, M645I, M645R, M645L, M645V, M645I,
621 7 S621R, S621R, S621R, S621N,
626 7 G626V, G626A, G626S,
620 7 S620G, S620I,
624 8 S624R, S624N, S624R, S624R,
624 8 S624R, S624N, S624R, S624R,
626 8 G626V, G626A, G626S,
625 8 V625E,
627 8 F627L, F627L, F627fsX, F627X, F627L,
623 8 T623I,
622 9 L622F,
627 9 F627L, F627L, F627fsX, F627X, F627L,
616 9 Y616S,
641 9 S641P, S641F,
619 9
622 9 L622F,
628 10 G628Del, G628D, G628V, G628R, G628S, G628A,
617 10 F617L, F617L, F617V, F617L,
644 10 V644F, V644I,
623 10 T623I,
620 10 S620G, S620I,
618 10 T618S, T618S,
617 10 F617L, F617L, F617V, F617L,
628 10 G628Del, G628D, G628V, G628R, G628S, G628A,
648 11 G648A,
649 11
642 11 I642V, I642Del,
652 11 Y652X,
645 11 M645L, M645I, M645I, M645R, M645L, M645V, M645I,
630 11 V630I, V630A, V630T,
627 11 F627L, F627L, F627fsX, F627X, F627L,
629 11 N629K, N629I, N629T, N629S, N629K, N629D,
632 11 P632S, P632A,
631 12 S631F,
652 12 Y652X,
618 12 T618S, T618S,
628 12 G628Del, G628D, G628V, G628R, G628S, G628A,
623 12 T623I,
621 12 S621R, S621R, S621R, S621N,
620 12 S620G, S620I,
645 12 M645L, M645I, M645I, M645R, M645L, M645V, M645I,
648 12 G648A,
630 12 V630I, V630A, V630T,
646 12
621 12 S621R, S621R, S621R, S621N,
644 12 V644F, V644I,
641 13 S641P, S641F,
631 13 S631F,
628 13 G628Del, G628D, G628V, G628R, G628S, G628A,
619 13
616 13 Y616S,
638 13 K638E, K638R, K638D, K638Del,
615 13 L615F, L615V,
649 13
643 13
647 13
629 13 N629K, N629I, N629T, N629S, N629K, N629D,
640 13 F640Del, F640L, F640L, F640L, F640V,
652 14 Y652X,
557 14
629 14 N629K, N629I, N629T, N629S, N629K, N629D,
632 14 P632S, P632A,
616 14 Y616S,
622 14 L622F,
614 14 A614T, A614V,
561 14 A561V, A561T, A561P,
613 14 T613K, T613M, T613L, T613A,
652 14 Y652X,
622 14 L622F,
649 14
641 15 S641P, S641F,
645 15 M645L, M645I, M645I, M645R, M645L, M645V, M645I,
656 15 F656L, F656L, F656L,
619 15