KCNH2 Variant F48V Detail

We estimate the penetrance of LQTS for KCNH2 F48V is 69%. We are unaware of any observations of this variant in individuals. F48V is not present in gnomAD. F48V 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 6 individuals with LQT2 and 4 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 F48V around 69% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.379 0.07 -2 0.935 72
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
LITERATURE, COHORT, AND GNOMAD: - 0 0 0 -
VARIANT FEATURES ALONE: - 10 4 6 -
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.

F48V has 66 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
48 0
49 5 C49R, C49G,
47 5 G47C, G47V,
52 5 C52W,
45 6 N45D, N45K, N45K,
51 6
28 6 K28E,
44 6 C44W, C44F, C44X,
30 7 I30T, I30Del,
129 7 F129C,
29 7 F29S, F29L, F29V, F29L, F29L,
50 7 E50X,
53 8 G53S, G53R,
59 8
46 8 D46Y, D46E, D46E,
54 8 Y54N, Y54X,
55 9 S55L,
56 9 R56Q,
43 9 Y43D, Y43C,
127 9
27 9 R27P, R27X,
69 9 L69P, L69Del,
128 10 N128S,
66 10 C66Y, C66G, C66R,
100 10 R100G, R100P, R100Q,
98 10
68 11 F68L, F68L, F68V, F68L,
41 11 V41A,
31 11 I31S,
60 11 M60T,
106 11 F106L, F106L, F106V, F106L,
108 11 C108Y,
58 11 E58K, E58D, E58D,
130 11 E130K,
101 12 K101E,
110 12 V110A,
57 12 A57P,
26 12 S26I,
64 12 C64R, C64Y,
126 12
42 13 I42N,
62 13 R62Q,
131 13 V131fsX, V131L, V131L,
22 13 F22S, F22Y,
32 13 A32T,
65 13 T65P,
19 13 I19F,
109 13 L109P, L109X, L109Q,
63 14 P63H,
111 14 D111V,
798 14 I798fsX,
23 14
70 14 H70Q, H70Q, H70R,
99 14 Y99S, Y99N,
104 14
96 14 I96T, I96V,
97 14
40 14
102 14 D102X, D102V, D102H,
67 15
859 15 T859M, T859R,
105 15
112 15 V112M,
107 15 L107P,
25 15 Q25P,
800 15