KCNH2 Variant G53R Detail

We estimate the penetrance of LQTS for KCNH2 G53R is 39%. This variant was found in a total of 8 carriers in 4 papers or gnomAD (version 4), 3 had LQTS. G53R is not present in gnomAD. We have tested the trafficking efficiency of this variant, 0% of WT with a standard error of 6%; 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. G53R 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 3 individuals with LQT2 and 7 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 G53R around 39% (6/18).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.081 0.996 -4 0.934 79
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
24103226 2014 1 0 1 Seizures
10973849 2000 1 0 1
15840476 2005 1 0 1
Personal Communication 2022 6 0 1 Seizures
LITERATURE, COHORT, AND GNOMAD: - 8 0 3 -
VARIANT FEATURES ALONE: - 10 7 3 -
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 None None None None
21536673 Xeno 5 None None None None

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

G53R has 40 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
53 0 G53S, G53R,
52 4 C52W,
54 4 Y54N, Y54X,
49 5 C49G, C49R,
101 5 K101E,
55 6 S55L,
51 7
100 7 R100Q, R100G, R100P,
50 7 E50X,
48 8
102 8 D102V, D102H, D102X,
58 8 E58D, E58D, E58K,
47 9 G47C, G47V,
59 10
68 10 F68V, F68L, F68L, F68L,
69 10 L69Del, L69P,
104 10
46 10 D46Y, D46E, D46E,
103 11
56 11 R56Q,
44 11 C44X, C44W, C44F,
57 11 A57P,
106 11 F106V, F106L, F106L, F106L,
45 11 N45D, N45K, N45K,
857 12 E857X,
99 12 Y99S, Y99N,
98 12
28 12 K28E,
105 13
66 13 C66G, C66R, C66Y,
60 13 M60T,
129 14 F129C,
741 14 K741R,
62 14 R62Q,
30 14 I30Del, I30T,
70 15 H70Q, H70Q, H70R,
29 15 F29L, F29L, F29S, F29L, F29V,
43 15 Y43C, Y43D,
859 15 T859R, T859M,
108 15 C108Y,