KCNH2 Variant S660W Detail

We estimate the penetrance of LQTS for KCNH2 S660W is 31%. We are unaware of any observations of this variant in individuals. S660W is not present in gnomAD. S660W 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 S660W around 31% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.777 1.0 -3 0.949 32
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.

S660W has 56 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
660 0 S660L,
661 4 A661V,
659 4
657 5 G657V, G657S,
663 5
654 6
653 6
664 6 Q664X,
662 6
658 6
657 7 G657V, G657S,
656 7 F656L, F656L, F656L,
658 9
650 9 L650X,
655 9
665 10 R665Q,
550 10
655 10
653 10
654 10
666 11
553 11 L553V,
649 11
651 11 M651K,
652 11 Y652X,
667 11 Y667X,
656 11 F656L, F656L, F656L,
652 11 Y652X,
660 11 S660L,
660 11 S660L,
661 12 A661V,
664 12 Q664X,
554 12
549 12 V549M,
659 12
668 12 S668L,
546 13
648 13 G648A,
547 13 A547T,
671 13 A671G, A671Del,
657 13 G657V, G657S,
661 14 A661V,
653 14
651 14 M651K,
663 14
671 14 A671G, A671Del,
557 14
662 14
647 14
553 14 L553V,
657 15 G657V, G657S,
670 15
548 15
646 15
552 15 L552S,
664 15 Q664X,