KCNH2 Variant A40V Detail

We estimate the penetrance of LQTS for KCNH2 A40V is 45%. We are unaware of any observations of this variant in individuals. A40V is not present in gnomAD. A40V 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 4 individuals with LQT2 and 6 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 A40V around 45% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.294 0.407 -1 0.8 52
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 6 4 -
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.

A40V has 56 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
40 0
41 4 V41A,
39 4 C39R, C39X,
32 5 A32T,
33 6 N33T,
63 6 P63H,
42 6 I42N,
36 6 V36X,
61 7 Q61R,
64 7 C64R, C64Y,
796 7 V796Del, V796L, V796L,
38 7
60 8 M60T,
62 8 R62Q,
34 8 A34T,
31 8 I31S,
37 9
795 9 V795I,
797 9 A797T,
35 9 R35W,
125 9
59 9
30 10 I30T, I30Del,
124 10 M124T, M124R,
65 10 T65P,
794 10 V794D, V794I,
66 10 C66G, C66R, C66Y,
798 11 I798fsX,
791 11 R791W, R791Q,
43 11 Y43D, Y43C,
860 12
44 12 C44F, C44X, C44W,
127 12
86 12 L86R,
789 12
123 12
57 13 A57P,
126 13
790 13
67 13
68 13 F68L, F68V, F68L, F68L,
56 13 R56Q,
788 13 E788D, E788K, E788D,
122 14
58 14 E58K, E58D, E58D,
859 14 T859R, T859M,
15 14 L15V,
29 14 F29L, F29L, F29V, F29S, F29L,
799 14 L799sp,
819 14 N819K, N819K,
83 14 A83fsX, A83P,
48 14
792 14
87 15 L87P,
82 15 I82Del, I82dup, I82Ins, I82T,
114 15 P114S,