KCNH2 Variant N33T Detail

We estimate the penetrance of LQTS for KCNH2 N33T is 59%. This variant was found in a total of 3 carriers in 3 papers or gnomAD, 2 had LQTS. N33T is not present in gnomAD. N33T has been functionally characterized in 2 papers. 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 5 individuals with LQT2 and 5 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 N33T around 59% (7/13).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.581 0.051 -1 0.851 62
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
11854117 2002 1 0 1
10973849 2000 2 0 2
14661677 2003 1 1
LITERATURE, COHORT, AND GNOMAD: - 3 1 2 -
VARIANT FEATURES ALONE: - 10 5 5 -
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.

Functional Data Homozygously 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).

PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Recov. Inact. Deactivation (%WT)
10187793 Xeno 7.5 19.6 None None
21536673 Xeno 35 3.5 11.5 None 0.666666667

Functional Data Heterozygously Collected

Functional parameters are the same as defined above.

PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Deactivation (%WT)
10187793 Xeno None None None
21536673 Xeno None None None

N33T has 59 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
33 0 N33T,
34 4 A34T,
32 5 A32T,
36 5 V36X,
124 5 M124R, M124T,
35 5 R35W,
39 6 C39X, C39R,
40 6
795 6 V795I,
123 6
42 7 I42N,
125 7
794 7 V794D, V794I,
796 7 V796L, V796Del, V796L,
31 8 I31S,
41 8 V41A,
122 9
38 10
64 10 C64Y, C64R,
37 10
797 10 A797T,
115 11 V115M,
15 11 L15V,
86 11 L86R,
798 11 I798fsX,
126 11
790 11
63 11 P63H,
12 11 N12D,
791 11 R791W, R791Q,
30 11 I30Del, I30T,
793 11 D793N,
121 11 A121fsX,
61 12 Q61R,
114 12 P114S,
788 12 E788D, E788K, E788D,
792 12
14 12
789 12
60 12 M60T,
127 12
43 12 Y43C, Y43D,
116 13 K116Q,
87 13 L87P,
65 13 T65P,
117 13
113 14 V113Del,
62 14 R62Q,
11 14 Q11L, Q11H, Q11H,
18 14 I18M,
112 14 V112M,
44 14 C44X, C44F, C44W,
89 14 A89G, A89V,
59 14
85 14 A85P, A85V,
29 15 F29L, F29L, F29V, F29S, F29L,
860 15
120 15
66 15 C66R, C66Y, C66G,