KCNH2 Variant V36L Detail

We estimate the penetrance of LQTS for KCNH2 V36L is 47%. We are unaware of any observations of this variant in individuals. V36L is not present in gnomAD. V36L 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 V36L around 47% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.991 0.002 0 0.473 55
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.

V36L has 41 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
36 0 V36X,
35 4 R35W,
37 5
34 5 A34T,
33 5 N33T,
39 5 C39X, C39R,
40 6
38 6
794 7 V794D, V794I,
32 8 A32T,
796 8 V796L, V796Del, V796L,
795 9 V795I,
791 9 R791Q, R791W,
124 10 M124T, M124R,
41 10 V41A,
123 10
42 10 I42N,
63 10 P63H,
125 10
64 11 C64Y, C64R,
792 11
61 11 Q61R,
122 11
793 12 D793N,
86 12 L86R,
797 12 A797T,
790 12
31 12 I31S,
87 13 L87P,
62 13 R62Q,
60 13 M60T,
789 13
65 13 T65P,
121 14 A121fsX,
819 14 N819K, N819K,
798 15 I798fsX,
30 15 I30Del, I30T,
788 15 E788D, E788K, E788D,
12 15 N12D,
115 15 V115M,
83 15 A83P, A83fsX,