KCNH2 Variant C49W Detail

We estimate the penetrance of LQTS for KCNH2 C49W is 26%. We are unaware of any observations of this variant in individuals. C49W 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. C49W 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 2 individuals with LQT2 and 8 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 C49W around 26% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.828 0.018 -4 0.859 74
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 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.

C49W has 52 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
49 0 C49R, C49G,
48 5
53 5 G53R, G53S,
50 5 E50X,
47 5 G47V, G47C,
52 5 C52W,
46 6 D46Y, D46E, D46E,
55 6 S55L,
45 7 N45K, N45K, N45D,
44 7 C44F, C44X, C44W,
51 7
56 7 R56Q,
54 7 Y54X, Y54N,
59 8
28 9 K28E,
58 10 E58D, E58K, E58D,
101 10 K101E,
57 10 A57P,
43 10 Y43D, Y43C,
29 11 F29V, F29S, F29L, F29L, F29L,
100 11 R100G, R100Q, R100P,
30 11 I30Del, I30T,
60 11 M60T,
129 11 F129C,
27 12 R27P, R27X,
857 12 E857X,
69 12 L69Del, L69P,
68 12 F68L, F68L, F68V, F68L,
859 13 T859R, T859M,
802 13
41 13 V41A,
803 13 D803X, D803Y,
102 13 D102H, D102V, D102X,
741 13 K741R,
106 13 F106L, F106L, F106V, F106L,
66 13 C66G, C66Y, C66R,
26 14 S26I,
98 14
800 14
62 14 R62Q,
31 14 I31S,
127 14
128 14 N128S,
801 14 K801T,
104 14
42 14 I42N,
798 14 I798fsX,
799 15 L799sp,
130 15 E130K,
108 15 C108Y,
23 15
19 15 I19F,