KCNH2 Variant S55A Detail

We estimate the penetrance of LQTS for KCNH2 S55A is 72%. We are unaware of any observations of this variant in individuals. S55A is not present in gnomAD. S55A 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 S55A around 72% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.691 0.0 0 0.593 80
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.

S55A has 50 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
55 0 S55L,
58 4 E58D, E58D, E58K,
57 5 A57P,
54 6 Y54N, Y54X,
56 6 R56Q,
49 6 C49G, C49R,
59 6
53 6 G53S, G53R,
857 7 E857X,
44 8 C44X, C44F, C44W,
52 8 C52W,
60 8 M60T,
859 9 T859M, T859R,
48 9
101 9 K101E,
46 10 D46E, D46Y, D46E,
858 10 I858V, I858T,
62 11 R62Q,
68 11 F68V, F68L, F68L, F68L,
50 11 E50X,
45 11 N45K, N45K, N45D,
741 11 K741R,
47 11 G47V, G47C,
803 11 D803Y, D803X,
856 12
51 12
804 12
61 12 Q61R,
41 12 V41A,
43 12 Y43D, Y43C,
855 12 S855R, S855R, S855R,
860 12
69 13 L69Del, L69P,
802 13
30 13 I30Del, I30T,
100 13 R100Q, R100P, R100G,
799 13 L799sp,
854 13
66 13 C66G, C66Y, C66R,
102 14 D102H, D102X, D102V,
800 14
42 14 I42N,
861 14 N861H, N861I,
798 14 I798fsX,
740 14 C740G, C740W,
29 14 F29S, F29V, F29L, F29L, F29L,
63 14 P63H,
742 15
797 15 A797T,
28 15 K28E,