KCNH2 Variant R35W Detail

We estimate the penetrance of LQTS for KCNH2 R35W is 23%. This variant was found in a total of 1 carriers in 1 papers or gnomAD (version 4), 1 had LQTS. R35W is not present in gnomAD. We have tested the trafficking efficiency of this variant, 89% of WT with a standard error of 20%; 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. R35W has been functionally characterized in 1 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 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 R35W around 23% (2/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.255 0.966 -4 0.87 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
26066609 2015 1 0 1
LITERATURE, COHORT, AND GNOMAD: - 1 0 1 -
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.

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)
26066609 Xeno 72 2.8 None None 1.352941176

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)
26066609 Xeno None None None

R35W has 41 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
35 0 R35W,
34 4 A34T,
36 4 V36X,
33 5 N33T,
794 7 V794D, V794I,
37 7
39 8 C39X, C39R,
123 8
795 9 V795I,
122 9
124 9 M124R, M124T,
40 9
38 9
32 9 A32T,
793 10 D793N,
792 10
796 10 V796Del, V796L, V796L,
125 10
121 11 A121fsX,
791 11 R791W, R791Q,
42 12 I42N,
86 12 L86R,
790 12
87 12 L87P,
41 13 V41A,
64 13 C64R, C64Y,
31 13 I31S,
115 13 V115M,
117 13
12 13 N12D,
797 14 A797T,
63 14 P63H,
120 14
116 14 K116Q,
114 14 P114S,
61 14 Q61R,
789 15
11 15 Q11L, Q11H, Q11H,
89 15 A89V, A89G,
15 15 L15V,
14 15