KCNH2 Variant W705G Detail

We estimate the penetrance of LQTS for KCNH2 W705G is 22%. We are unaware of any observations of this variant in individuals. W705G is not present in gnomAD. W705G 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 2 individuals with LQT2 and 8 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 W705G around 22% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-12.373 1.0 -3 0.954 22
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 8 2 -
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.

W705G has 46 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
705 0 W705fsX, W705X,
706 5 S706C, S706F,
709 5
710 5
673 6
704 6 A704V, A704T,
708 6
701 7
669 7 G669C, G669X, G669R,
702 7
672 7 R672C, R672H,
711 8 I711V,
670 8
703 9
676 9 Q676fsX, Q676X,
707 9
677 10 M677T,
674 10 H674fsX, H674Y,
671 10 A671Del, A671G,
668 10 S668L,
700 11
4 11
712 11 D712N,
675 11
682 11 E682X,
686 11
713 12 M713V,
719 13
699 13 E699D, E699D,
698 13 E698X, E698K,
680 13
667 13 Y667X,
540 14 D540fsX,
720 14
679 14 R679W, R679Q,
762 14
3 14
697 14 L697X,
678 14
478 14 A478D,
679 14 R679W, R679Q,
681 15 R681W,
666 15
543 15 S543fsX,
685 15 R685P, R685C, R685H,
683 15