A1116V Summary

KCNH2 A1116V was found in 2 papers (see below) with a total of 15 carriers: 3 had LQT2. A1116V is present in 6 out of 194268 alleles in gnomAD (0.003089%). A1116V has been functionally characterized in 2 papers. Given the functional data available, we estimate this variant has "LOF" in vitro character. (LOF and GOF denote loss-of-function and gain-of-function, respectively). This residue is located in a Mild_Hotspot region for LQT2.

In silico predictions, functional data (if available), and location in structure are equivalent to observing 8 individuals unaffected with LQT2 and 2 individuals affected with LQT2.

A1116V Reported Clinical Data

PMID Year Carriers Unaffected LQT2 Other disease
16116052 2005 4 3 1
Italy Cohort 2020 9 6 3
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts.

A1116V Reported Functional Data: heterozygously collected

Steady state (S.S.) and peak tail current are relative % to wildtype (100% being no different from wildtype). V0.5 act/inact are the voltages at which half of the maximal current is reached during an activation and inactivation protocol, each is in units of mV and relative to wildtype. Recovery from inactivation (Rec. inact.) and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless).

PMID Year Cell type S.S. peak current (%WT) Peak tail current (%WT) V0.5 act V0.5 inact Rec. inact. (%WT) Deactivation (%WT)
16116052 2005 CHO 67.2
19673885 2010 HEK293

A1116V Reported Functional Data: homozygously collected

PMID Year Cell type S.S. peak current (%WT) Peak tail current (%WT) V0.5 act V0.5 inact Rec. inact. (%WT) Deactivation (%WT)
16116052 2005 CHO -6.20
19673885 2010 HEK293 -0.10 -1.60 107.7 105.4

A1116V Predictions

PROVEAN scores less than -2 are considered deleterious. REVEL scores higher than 0.5 or 0.75 is 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. PAM scores reflect the chemistry difference between WT and variant amino acid (more negative being greater difference between the two). BLAST-PSSM reflects the evolutionary conservation of residue substitutions, more negative numbers indicate fewer observations of the specific substitution than is expected.

PAM Score REVEL Score PROVEAN Score Polyphen2 Score BLAST-PSSM
-2 0.565 -1.227 0.007 -1

A1116V has 30 neighbors (found in individuals) within 15 ångströms

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. This results from the fact that the functional Kv11.1 channel 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.

ResidueNumber Distance(Å) Variants
1101 14.7 P1101fsX
1102 14.2
1103 13.7 L1103P
1104 13.2 T1104I
1105 12.6 L1105S
1106 12
1107 11.4 S1107L
1108 10.7 L1108V
1109 10.1
1110 9.3 Q1110P
1111 8.5 V1111F
1112 7.6
1113 6.6
1114 5.4
1115 3.8 M1115T
1117 3.8 C1117fsX
1118 5.4
1119 6.6 E1119Q E1119V
1120 7.6
1121 8.5
1122 9.3 P1122fsX P1122L P1122R
1123 10.1 G1123R
1124 10.7
1125 11.4 P1125A P1125X
1126 12 E1126fsX
1127 12.6
1128 13.2
1129 13.7
1130 14.2
1131 14.7 G1131V