KCNH2 Variant R56W Detail

We estimate the penetrance of LQTS for KCNH2 R56W is 77%. We are unaware of any observations of this variant in individuals. R56W is not present in gnomAD. R56W 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 R56W around 77% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.087 0.991 -4 0.77 76
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.

R56W has 62 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
56 0 R56Q,
44 4 C44W, C44X, C44F,
55 6 S55L,
859 6 T859R, T859M,
60 6 M60T,
57 6 A57P,
803 7 D803Y, D803X,
59 7
43 7 Y43C, Y43D,
49 7 C49G, C49R,
46 8 D46E, D46E, D46Y,
45 8 N45K, N45K, N45D,
799 8 L799sp,
800 8
857 9 E857X,
58 9 E58D, E58K, E58D,
798 9 I798fsX,
48 9
802 9
804 9
860 10
41 10 V41A,
858 10 I858T, I858V,
42 10 I42N,
797 10 A797T,
47 10 G47C, G47V,
801 10 K801T,
54 11 Y54X, Y54N,
30 11 I30T, I30Del,
53 11 G53R, G53S,
61 11 Q61R,
782 11 I782N, I782fsX,
29 11 F29S, F29L, F29L, F29V, F29L,
52 11 C52W,
31 11 I31S,
50 12 E50X,
741 12 K741R,
805 12 F805S, F805C,
62 12 R62Q,
787 12
796 13 V796Del, V796L, V796L,
856 13
786 13
19 13 I19F,
789 13
740 13 C740G, C740W,
785 13 G785D, G785S, G785fsX,
40 13
861 13 N861I, N861H,
781 13
51 14
788 14 E788D, E788K, E788D,
28 14 K28E,
783 14 S783P,
806 14 G806R, G806R,
68 14 F68L, F68L, F68L, F68V,
32 14 A32T,
101 14 K101E,
855 15 S855R, S855R, S855R,
27 15 R27P, R27X,
63 15 P63H,
66 15 C66Y, C66G, C66R,