KCNH2 Variant C39Y Detail

We estimate the penetrance of LQTS for KCNH2 C39Y is 38%. We are unaware of any observations of this variant in individuals. C39Y is not present in gnomAD. C39Y has not been functionally characterized. This residue is located in a Mild_Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 3 individuals with LQT2 and 7 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 C39Y around 38% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.595 0.993 -4 0.848 37
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 7 3 -
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.

C39Y 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
39 0 C39R, C39X,
40 4
38 5
64 5 C64Y, C64R,
36 5 V36X,
32 6 A32T,
34 6 A34T,
33 6 N33T,
63 6 P63H,
125 7
41 7 V41A,
37 7
35 8 R35W,
86 8 L86R,
65 8 T65P,
124 9 M124R, M124T,
42 10 I42N,
31 10 I31S,
62 10 R62Q,
796 10 V796L, V796Del, V796L,
87 10 L87P,
66 10 C66Y, C66G, C66R,
83 10 A83P, A83fsX,
61 11 Q61R,
123 11
122 11
30 11 I30Del, I30T,
795 11 V795I,
127 11
794 11 V794I, V794D,
85 12 A85P, A85V,
60 12 M60T,
82 12 I82T, I82Del, I82Ins, I82dup,
126 12
67 12
59 13
114 13 P114S,
112 13 V112M,
797 13 A797T,
791 14 R791W, R791Q,
88 14
115 14 V115M,
89 14 A89G, A89V,
68 14 F68L, F68L, F68V, F68L,
84 14
113 14 V113Del,
43 14 Y43D, Y43C,
121 14 A121fsX,
798 14 I798fsX,
44 15 C44X, C44W, C44F,