KCNH2 Variant S668L Detail

We estimate the penetrance of LQTS for KCNH2 S668L is 11%. This variant was found in a total of 2 carriers in 0 papers or gnomAD, 0 had LQTS. S668L is present in 2 alleles in gnomAD. S668L 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 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 S668L around 11% (1/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.815 0.999 -3 0.919 7
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: - 2 2 0 -
VARIANT FEATURES ALONE: - 10 9 1 -
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.

S668L has 44 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
668 0 S668L,
669 4 G669X, G669R, G669C,
672 5 R672H, R672C,
671 5 A671Del, A671G,
670 6
664 7 Q664X,
667 7 Y667X,
666 7
665 7 R665Q,
710 9
663 9
678 9
709 10
661 10 A661V,
675 10
673 10
682 10 E682X,
662 10
705 10 W705X, W705fsX,
674 10 H674fsX, H674Y,
679 11 R679W, R679Q,
675 11
711 11 I711V,
676 12 Q676fsX, Q676X,
546 12
660 12 S660L,
658 13
708 13
712 13 D712N,
674 13 H674fsX, H674Y,
676 13 Q676fsX, Q676X,
665 14 R665Q,
661 14 A661V,
547 14 A547T,
706 14 S706C, S706F,
681 14 R681W,
659 14
671 14 A671Del, A671G,
677 14 M677T,
677 15 M677T,
657 15 G657V, G657S,
654 15
680 15
685 15 R685P, R685H, R685C,