KCNH2 Variant C52W Detail

We estimate the penetrance of LQTS for KCNH2 C52W is 27%. This variant was found in a total of 11 carriers in 0 papers or gnomAD, 0 had LQTS. C52W is present in 11 alleles in gnomAD. C52W 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 5 individuals with LQT2 and 5 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 C52W around 27% (5/21).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.559 0.998 -3 0.545 57
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: - 11 11 0 -
VARIANT FEATURES ALONE: - 10 5 5 -
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.

C52W has 53 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
52 0 C52W,
53 4 G53S, G53R,
51 4
54 5 Y54X, Y54N,
49 5 C49G, C49R,
48 5
100 6 R100G, R100Q, R100P,
101 7 K101E,
69 7 L69Del, L69P,
50 7 E50X,
55 8 S55L,
47 8 G47C, G47V,
68 8 F68V, F68L, F68L, F68L,
106 9 F106L, F106L, F106L, F106V,
102 9 D102H, D102V, D102X,
59 9
98 9
104 10
58 10 E58D, E58K, E58D,
28 10 K28E,
99 10 Y99N, Y99S,
103 10
129 10 F129C,
44 10 C44F, C44X, C44W,
45 10 N45K, N45K, N45D,
66 11 C66Y, C66G, C66R,
46 11 D46E, D46Y, D46E,
105 11
56 11 R56Q,
30 12 I30T, I30Del,
108 12 C108Y,
70 12 H70Q, H70R, H70Q,
57 12 A57P,
97 12
29 13 F29L, F29L, F29L, F29S, F29V,
62 13 R62Q,
60 13 M60T,
131 13 V131fsX, V131L, V131L,
67 13
127 14
130 14 E130K,
41 14 V41A,
107 14 L107P,
71 14 G71R, G71E, G71W, G71R,
96 14 I96T, I96V,
27 14 R27P, R27X,
43 14 Y43C, Y43D,
128 14 N128S,
65 14 T65P,
110 14 V110A,
64 15 C64R, C64Y,
63 15 P63H,
857 15 E857X,