KCNQ1 Variant N112I Detail

We estimate the penetrance of LQTS for KCNQ1 N112I is 61%. We are unaware of any observations of this variant in individuals. N112I is not present in gnomAD. N112I has not been functionally characterized. This residue is located in a Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 6 individuals with LQT1 and 4 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 N112I around 61% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.24 0.899 -3 0.87 65
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 4 6 -
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.

N112I has 39 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
112 0
116 5
111 5 Y111C,
108 5 G108S,
117 6 P117L,
110 6 V110I,
113 7
115 7 E115A, E115G,
114 7
109 8 R109C, R109L,
118 8
180 8
122 8 C122Y,
177 9 S177F,
119 9 G119R, G119V,
181 9 R181C,
107 10 Q107H, Q107H,
106 10
174 10 R174H, R174C, R174L,
178 10 A178T, A178del,
244 11
105 11
121 11
126 11 H126D,
179 11 G179S,
243 12 R243H, R243C, R243P, R243S,
173 12
125 12
184 13 Y184S, Y184C, Y184D, Y184H,
193 13 F193L, F193L, F193L,
170 13
123 14
104 14 T104A, T104I,
175 14 L175I,
182 14
120 14 W120C, W120C,
176 14
183 14 K183R,
124 15