KCNQ1 Variant A102E Detail

We estimate the penetrance of LQTS for KCNQ1 A102E is 16%. We are unaware of any observations of this variant in individuals. A102E is not present in gnomAD. A102E has not been functionally characterized. This residue is located in a Non_Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 1 individuals with LQT1 and 9 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 A102E around 16% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.74 0.771 -1 0.662 10
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 LQT1 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.

A102E has 31 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. This results from the fact that the functional KV7.1 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.

Neighbor Distance (Angstroms) Variants Observed in Individuals
102 0
101 4
103 4
100 5
104 5 T104A, T104I,
99 7 P99R, P99Q,
105 7
98 8 R98H,
106 8
97 8
107 8 Q107H, Q107H,
96 9 T96R,
108 9 G108S,
95 10 S95G,
109 10 R109C, R109L,
94 11
110 11 V110I,
93 11 I93V,
111 11 Y111C,
92 12 S92P,
112 12
91 13 V91L,
113 13
90 13
114 13
89 14 P89T, P89L,
115 14 E115A, E115G,
88 14 D88E, D88E,
116 14
87 15
117 15 P117L,