KCNH2 Variant S55L Detail

We estimate the penetrance of LQTS for KCNH2 S55L is 52%. This variant was found in a total of 12 carriers in 4 papers or gnomAD (version 4), 10 had LQTS. S55L is not present in gnomAD. We have tested the trafficking efficiency of this variant, 0% of WT with a standard error of 9%; 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. S55L 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 2 individuals with LQT2 and 8 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 S55L around 52% (12/22).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.482 0.382 -3 0.927 80
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
18508782 2008 4 2 2
Japan Cohort 2020 3 0 3
29330128 2018 4 0 4
15840476 2005 1 0 1
LITERATURE, COHORT, AND GNOMAD: - 12 2 10 -
VARIANT FEATURES ALONE: - 10 8 2 -
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)
29330128 CHO 13 9.9 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)
29330128 CHO None None None

S55L has 50 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
55 0 S55L,
58 4 E58D, E58K, E58D,
57 5 A57P,
54 6 Y54X, Y54N,
56 6 R56Q,
49 6 C49G, C49R,
59 6
53 6 G53R, G53S,
857 7 E857X,
44 8 C44X, C44W, C44F,
52 8 C52W,
60 8 M60T,
859 9 T859M, T859R,
48 9
101 9 K101E,
46 10 D46Y, D46E, D46E,
858 10 I858T, I858V,
62 11 R62Q,
68 11 F68L, F68V, F68L, F68L,
50 11 E50X,
45 11 N45D, N45K, N45K,
741 11 K741R,
47 11 G47V, G47C,
803 11 D803X, D803Y,
856 12
51 12
804 12
61 12 Q61R,
41 12 V41A,
43 12 Y43C, Y43D,
855 12 S855R, S855R, S855R,
860 12
69 13 L69Del, L69P,
802 13
30 13 I30Del, I30T,
100 13 R100G, R100P, R100Q,
799 13 L799sp,
854 13
66 13 C66G, C66R, C66Y,
102 14 D102V, D102X, D102H,
800 14
42 14 I42N,
861 14 N861I, N861H,
798 14 I798fsX,
740 14 C740G, C740W,
29 14 F29L, F29S, F29V, F29L, F29L,
63 14 P63H,
742 15
797 15 A797T,
28 15 K28E,