KCNH2 Variant C66Y Detail

We estimate the penetrance of LQTS for KCNH2 C66Y is 86%. This variant was found in a total of 2 carriers in 1 papers or gnomAD, 2 had LQTS. C66Y is not present in gnomAD. C66Y 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 8 individuals with LQT2 and 2 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 C66Y around 86% (10/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.455 1.0 -3 0.895 88
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
France Cohort 2020 2 0 2
LITERATURE, COHORT, AND GNOMAD: - 2 0 2 -
VARIANT FEATURES ALONE: - 10 2 8 -
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.

C66Y has 69 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
66 0 C66R, C66Y, C66G,
65 4 T65P,
67 5
68 5 F68L, F68L, F68L, F68V,
69 5 L69P, L69Del,
63 6 P63H,
64 6 C64Y, C64R,
70 6 H70Q, H70R, H70Q,
62 8 R62Q,
98 8
59 9
82 9 I82T, I82Ins, I82Del, I82dup,
41 9 V41A,
30 9 I30T, I30Del,
127 10
79 10 A79Del, A79S, A79fsX, A79T,
48 10
54 10 Y54N, Y54X,
39 10 C39X, C39R,
40 10
52 11 C52W,
96 11 I96V, I96T,
129 11 F129C,
83 11 A83P, A83fsX,
110 11 V110A,
71 11 G71R, G71E, G71W, G71R,
32 11 A32T,
38 12
58 12 E58K, E58D, E58D,
60 12 M60T,
74 12 T74fsX, T74M,
97 12
99 12 Y99S, Y99N,
86 12 L86R,
80 12 A80P,
108 12 C108Y,
125 13
78 13 A78T, A78P,
61 13 Q61R,
51 13
31 13 I31S,
44 13 C44X, C44F, C44W,
106 13 F106L, F106L, F106V, F106L,
112 13 V112M,
53 13 G53S, G53R,
94 13 V94L, V94L, V94A,
100 13 R100P, R100G, R100Q,
101 13 K101E,
49 13 C49R, C49G,
55 13 S55L,
85 14 A85V, A85P,
42 14 I42N,
29 14 F29V, F29L, F29S, F29L, F29L,
128 14 N128S,
57 14 A57P,
76 14
81 14 Q81H, Q81P, Q81X, Q81H, Q81E,
126 14
28 14 K28E,
75 14 Q75X,
109 15 L109Q, L109X, L109P,
72 15 P72S, P72Q, P72T, P72R,
111 15 D111V,
73 15 R73fsX, R73H, R73G, R73C,
43 15 Y43C, Y43D,
33 15 N33T,
45 15 N45D, N45K, N45K,
105 15
56 15 R56Q,