KCNH2 Variant A34G Detail

We estimate the penetrance of LQTS for KCNH2 A34G is 14%. We are unaware of any observations of this variant in individuals. A34G is not present in gnomAD. We have tested the trafficking efficiency of this variant, 74% of WT with a standard error of 15%; 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. A34G 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 A34G around 14% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.487 0.989 -1 0.907 66
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 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.

A34G has 51 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
34 0 A34T,
35 4 R35W,
33 4 N33T,
36 5 V36X,
39 6 C39R, C39X,
123 6
122 6
124 6 M124T, M124R,
32 7 A32T,
125 7
40 8
37 9
86 9 L86R,
38 9
794 9 V794I, V794D,
121 9 A121fsX,
795 9 V795I,
87 10 L87P,
64 10 C64Y, C64R,
115 11 V115M,
42 11 I42N,
31 11 I31S,
796 11 V796L, V796L, V796Del,
114 11 P114S,
41 11 V41A,
116 12 K116Q,
89 12 A89G, A89V,
63 12 P63H,
126 12
88 12
117 12
85 12 A85P, A85V,
120 13
793 13 D793N,
792 13
83 13 A83fsX, A83P,
65 13 T65P,
791 13 R791W, R791Q,
127 13
797 14 A797T,
15 14 L15V,
12 14 N12D,
30 14 I30Del, I30T,
113 14 V113Del,
14 14
112 14 V112M,
790 14
90 14 E90K,
61 14 Q61R,
119 15 D119G, D119H,
798 15 I798fsX,