KCNH2 Variant N45T Detail

We estimate the penetrance of LQTS for KCNH2 N45T is 60%. We are unaware of any observations of this variant in individuals. N45T is not present in gnomAD. N45T 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 6 individuals with LQT2 and 4 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 N45T around 60% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.932 0.335 -1 0.827 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 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.

N45T has 55 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
45 0 N45D, N45K, N45K,
46 5 D46E, D46Y, D46E,
47 5 G47C, G47V,
44 5 C44W, C44F, C44X,
29 5 F29V, F29L, F29S, F29L, F29L,
48 6
43 6 Y43D, Y43C,
49 7 C49G, C49R,
27 7 R27P, R27X,
28 7 K28E,
30 8 I30Del, I30T,
56 8 R56Q,
50 8 E50X,
19 9 I19F,
23 9
26 9 S26I,
22 10 F22S, F22Y,
31 10 I31S,
129 10 F129C,
51 10
128 10 N128S,
52 10 C52W,
800 11
798 11 I798fsX,
59 11
55 11 S55L,
801 11 K801T,
127 11
60 11 M60T,
53 11 G53R, G53S,
42 12 I42N,
41 12 V41A,
25 12 Q25P,
24 12
126 12
803 12 D803Y, D803X,
799 12 L799sp,
802 12
18 12 I18M,
54 13 Y54N, Y54X,
130 13 E130K,
57 13 A57P,
21 13
16 13 D16A,
15 13 L15V,
20 13 R20G, R20L,
32 14 A32T,
859 14 T859M, T859R,
786 14
797 14 A797T,
785 14 G785fsX, G785S, G785D,
58 14 E58K, E58D, E58D,
111 15 D111V,
17 15
66 15 C66G, C66Y, C66R,