KCNH2 Variant F29L Detail

We estimate the penetrance of LQTS for KCNH2 F29L is 73%. This variant was found in a total of 38 carriers in 6 papers or gnomAD, 28 had LQTS. F29L is not present in gnomAD. F29L has been functionally characterized in 4 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 7 individuals with LQT2 and 3 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 F29L around 73% (35/48).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.481 0.0 -1 0.927 82
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
26403377 2015 33 7 26
24606995 2014 1 0 1
10973849 2000 1 0 1
15840476 2005 1 0 1
22882672 2012 9 3
LITERATURE, COHORT, AND GNOMAD: - 38 10 28 -
VARIANT FEATURES ALONE: - 10 3 7 -
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 0 None None None None
23721480 CHO None None None None
26403377 HEK293 25 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
23721480 CHO None None None
26403377 HEK293 60 81 None None None

F29L has 64 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
29 0 F29V, F29L, F29S, F29L, F29L,
30 5 I30T, I30Del,
45 5 N45D, N45K, N45K,
27 6 R27P, R27X,
43 6 Y43C, Y43D,
128 6 N128S,
22 6 F22S, F22Y,
28 6 K28E,
31 7 I31S,
127 7
126 7
19 7 I19F,
48 7
129 7 F129C,
44 7 C44X, C44F, C44W,
47 8 G47V, G47C,
18 9 I18M,
23 9
26 9 S26I,
46 10 D46Y, D46E, D46E,
25 10 Q25P,
111 10 D111V,
21 10
49 11 C49R, C49G,
32 11 A32T,
42 11 I42N,
113 11 V113Del,
41 11 V41A,
798 11 I798fsX,
15 11 L15V,
24 11
56 11 R56Q,
130 11 E130K,
51 12
112 12 V112M,
125 12
110 12 V110A,
59 12
124 12 M124R, M124T,
50 12 E50X,
16 12 D16A,
17 12
64 13 C64Y, C64R,
60 13 M60T,
52 13 C52W,
20 13 R20G, R20L,
109 13 L109Q, L109X, L109P,
800 13
114 13 P114S,
115 13 V115M,
108 13 C108Y,
66 14 C66R, C66Y, C66G,
797 14 A797T,
14 14
40 14
799 14 L799sp,
801 14 K801T,
55 14 S55L,
131 15 V131L, V131fsX, V131L,
786 15
33 15 N33T,
53 15 G53S, G53R,
98 15
69 15 L69P, L69Del,