KCNH2 Variant F68L Detail

We estimate the penetrance of LQTS for KCNH2 F68L is 82%. This variant was found in a total of 5 carriers in 2 papers or gnomAD, 5 had LQTS. F68L is not present in gnomAD. F68L has not been functionally characterized. 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 F68L around 82% (12/15).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.031 0.999 0 0.894 81
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
Japan Cohort 2020 4 0 4
21063070 2010 1 0 1
LITERATURE, COHORT, AND GNOMAD: - 5 0 5 -
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.

F68L has 49 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
68 0 F68L, F68L, F68V, F68L,
69 4 L69P, L69Del,
66 5 C66R, C66G, C66Y,
67 5
54 7 Y54X, Y54N,
70 7 H70Q, H70Q, H70R,
62 7 R62Q,
59 8
63 8 P63H,
58 8 E58D, E58D, E58K,
52 8 C52W,
65 9 T65P,
98 9
101 9 K101E,
99 10 Y99N, Y99S,
71 10 G71R, G71W, G71R, G71E,
53 10 G53S, G53R,
64 10 C64Y, C64R,
48 11
55 11 S55L,
100 11 R100P, R100Q, R100G,
41 11 V41A,
57 12 A57P,
60 12 M60T,
51 12
49 12 C49R, C49G,
30 12 I30Del, I30T,
103 12
74 12 T74fsX, T74M,
106 12 F106V, F106L, F106L, F106L,
97 12
61 13 Q61R,
102 13 D102V, D102H, D102X,
96 13 I96T, I96V,
40 13
44 13 C44F, C44W, C44X,
72 13 P72R, P72S, P72Q, P72T,
129 13 F129C,
79 13 A79S, A79fsX, A79T, A79Del,
104 13
105 14
127 14
82 14 I82Ins, I82T, I82dup, I82Del,
56 14 R56Q,
39 14 C39X, C39R,
38 14
108 14 C108Y,
73 14 R73H, R73G, R73fsX, R73C,
110 15 V110A,