KCNH2 Variant V41I Detail

We estimate the penetrance of LQTS for KCNH2 V41I is 15%. This variant was found in a total of 1 carriers in 0 papers or gnomAD (version 4), 0 had LQTS. V41I is present in 1 alleles in gnomAD. We have tested the trafficking efficiency of this variant, 121% of WT with a standard error of 14%; 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. V41I 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 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 V41I around 15% (1/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
0.426 0.0 6 0.411 49
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: - 1 0 0 -
VARIANT FEATURES ALONE: - 10 9 1 -
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.

V41I has 66 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
41 0 V41A,
40 4
42 5 I42N,
60 5 M60T,
32 6 A32T,
59 6
31 6 I31S,
30 7 I30T, I30Del,
61 7 Q61R,
64 7 C64Y, C64R,
63 7 P63H,
62 7 R62Q,
39 7 C39R, C39X,
44 8 C44X, C44F, C44W,
796 8 V796L, V796Del, V796L,
43 8 Y43D, Y43C,
33 8 N33T,
797 8 A797T,
798 9 I798fsX,
66 9 C66Y, C66G, C66R,
56 10 R56Q,
127 10
125 10
36 10 V36X,
795 10 V795I,
65 10 T65P,
57 10 A57P,
38 10
124 10 M124R, M124T,
48 11
860 11
29 11 F29V, F29L, F29L, F29S, F29L,
34 11 A34T,
126 11
58 11 E58D, E58K, E58D,
68 11 F68L, F68L, F68L, F68V,
859 11 T859M, T859R,
45 12 N45K, N45K, N45D,
789 12
55 12 S55L,
799 12 L799sp,
794 12 V794D, V794I,
35 13 R35W,
788 13 E788D, E788K, E788D,
67 13
49 13 C49G, C49R,
37 13
15 13 L15V,
54 13 Y54N, Y54X,
69 13 L69P, L69Del,
86 13 L86R,
129 13 F129C,
791 13 R791W, R791Q,
123 14
52 14 C52W,
19 14 I19F,
790 14
800 14
128 14 N128S,
112 14 V112M,
803 15 D803Y, D803X,
47 15 G47V, G47C,
861 15 N861I, N861H,
82 15 I82Del, I82Ins, I82dup, I82T,
46 15 D46E, D46E, D46Y,
28 15 K28E,