KCNH2 Variant L51M Detail

We estimate the penetrance of LQTS for KCNH2 L51M is 41%. We are unaware of any observations of this variant in individuals. L51M is not present in gnomAD. L51M 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 4 individuals with LQT2 and 6 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L51M around 41% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
0.477 0.0 8 0.462 70
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 6 4 -
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.

L51M has 45 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
51 0
52 4 C52W,
48 6
50 6 E50X,
100 6 R100G, R100Q, R100P,
47 6 G47V, G47C,
106 7 F106L, F106L, F106V, F106L,
49 7 C49R, C49G,
28 7 K28E,
53 7 G53S, G53R,
129 8 F129C,
98 9
108 9 C108Y,
54 9 Y54N, Y54X,
131 9 V131fsX, V131L, V131L,
69 10 L69P, L69Del,
104 10
130 10 E130K,
45 10 N45K, N45D, N45K,
105 10
101 10 K101E,
46 11 D46E, D46Y, D46E,
102 11 D102V, D102X, D102H,
99 11 Y99S, Y99N,
27 11 R27P, R27X,
107 11 L107P,
29 12 F29L, F29L, F29S, F29L, F29V,
97 12
103 12
128 12 N128S,
55 12 S55L,
30 12 I30Del, I30T,
44 12 C44X, C44F, C44W,
68 12 F68L, F68L, F68L, F68V,
59 12
109 12 L109X, L109Q, L109P,
66 13 C66G, C66R, C66Y,
110 13 V110A,
26 13 S26I,
96 13 I96T, I96V,
127 13
56 14 R56Q,
70 14 H70Q, H70Q, H70R,
58 14 E58D, E58D, E58K,
43 15 Y43C, Y43D,