KCNH2 Variant Y812S Detail

We estimate the penetrance of LQTS for KCNH2 Y812S is 9%. This variant was found in a total of 1 carriers in 0 papers or gnomAD (version 4), 0 had LQTS. Y812S is present in 1 alleles in gnomAD. We have tested the trafficking efficiency of this variant, 98% of WT with a standard error of 4%; in our analysis we used SE < 20% as 'high quality'. Approximately below 50% of WT is considered PS3 moderate and below 30% is PS3 strong. Y812S has not been functionally characterized. This residue is located in a Non_Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 0 individuals with LQT2 and 10 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 Y812S around 9% (0/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.013 0.274 -2 0.699 10
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: - 1 1 0 -
VARIANT FEATURES ALONE: - 10 10 0 -
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.

Y812S has 30 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
812 0 Y812S,
811 5
813 6
814 6
807 7 E807X,
816 7 G816V,
808 7
809 8
815 8
810 8
863 9 R863X, R863P,
861 9 N861H, N861I,
817 10
776 10 L776P, L776I,
862 10 L862P,
835 10 R835fsX, R835Q, R835W,
806 11 G806R, G806R,
818 12 S818A, S818W, S818L,
775 12
853 13 W853X,
777 13
858 13 I858V, I858T,
844 13 M844V,
778 14 A778T,
819 14 N819K, N819K,
839 14
779 14
773 14
774 15 D774Y, D774X,
860 15