KCNH2 Variant C44G Detail

We estimate the penetrance of LQTS for KCNH2 C44G is 72%. We are unaware of any observations of this variant in individuals. C44G is not present in gnomAD. C44G 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 C44G around 72% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.731 0.999 -4 0.973 71
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 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.

C44G has 70 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
44 0 C44W, C44F, C44X,
43 4 Y43D, Y43C,
56 4 R56Q,
45 5 N45D, N45K, N45K,
60 6 M60T,
48 6
59 7
30 7 I30T, I30Del,
49 7 C49R, C49G,
46 7 D46Y, D46E, D46E,
29 7 F29S, F29L, F29V, F29L, F29L,
41 8 V41A,
798 8 I798fsX,
42 8 I42N,
31 8 I31S,
55 8 S55L,
47 8 G47C, G47V,
57 9 A57P,
799 9 L799sp,
800 9
859 9 T859M, T859R,
803 10 D803Y, D803X,
797 10 A797T,
19 10 I19F,
52 10 C52W,
58 10 E58K, E58D, E58D,
28 11 K28E,
54 11 Y54N, Y54X,
53 11 G53S, G53R,
32 11 A32T,
50 11 E50X,
127 11
61 11 Q61R,
801 11 K801T,
27 12 R27P, R27X,
40 12
860 12
802 12
62 12 R62Q,
51 12
129 12 F129C,
796 12 V796Del, V796L, V796L,
126 12
64 13 C64R, C64Y,
857 13 E857X,
786 13
66 13 C66Y, C66G, C66R,
15 13 L15V,
128 13 N128S,
22 13 F22S, F22Y,
804 13
23 13
787 13
68 13 F68L, F68L, F68V, F68L,
788 13 E788D, E788D, E788K,
63 13 P63H,
18 13 I18M,
789 14
858 14 I858V, I858T,
782 14 I782fsX, I782N,
785 14 G785fsX, G785D, G785S,
69 14 L69P, L69Del,
16 14 D16A,
795 14 V795I,
26 14 S26I,
124 14 M124R, M124T,
33 14 N33T,
125 15
805 15 F805S, F805C,
39 15 C39R, C39X,