KCNH2 Variant V59E Detail

We estimate the penetrance of LQTS for KCNH2 V59E is 75%. We are unaware of any observations of this variant in individuals. V59E is not present in gnomAD. V59E 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 V59E around 75% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.953 0.866 -4 0.839 73
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.

V59E has 57 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
59 0
60 5 M60T,
58 5 E58D, E58D, E58K,
62 6 R62Q,
57 6 A57P,
55 6 S55L,
41 6 V41A,
44 7 C44F, C44W, C44X,
54 7 Y54N, Y54X,
56 7 R56Q,
68 8 F68L, F68V, F68L, F68L,
61 8 Q61R,
48 8
49 8 C49R, C49G,
66 9 C66Y, C66G, C66R,
63 9 P63H,
30 9 I30T, I30Del,
52 9 C52W,
40 9
53 10 G53S, G53R,
42 10 I42N,
859 10 T859R, T859M,
43 10 Y43C, Y43D,
69 10 L69Del, L69P,
64 10 C64Y, C64R,
45 11 N45K, N45D, N45K,
31 11 I31S,
860 11
67 11
65 11 T65P,
101 11 K101E,
32 12 A32T,
857 12 E857X,
797 12 A797T,
798 12 I798fsX,
29 12 F29S, F29L, F29L, F29L, F29V,
47 12 G47V, G47C,
796 12 V796L, V796L, V796Del,
51 12
46 12 D46Y, D46E, D46E,
127 12
39 13 C39X, C39R,
858 13 I858T, I858V,
799 13 L799sp,
129 13 F129C,
803 13 D803X, D803Y,
50 14 E50X,
861 14 N861I, N861H,
98 14
70 14 H70Q, H70R, H70Q,
38 14
28 14 K28E,
100 14 R100P, R100Q, R100G,
804 14
33 14 N33T,
800 15
789 15