KCNH2 Variant S654R Detail

We estimate the penetrance of LQTS for KCNH2 S654R is 48%. We are unaware of any observations of this variant in individuals. S654R is not present in gnomAD. S654R has not been functionally characterized. This residue is located in a Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 4 individuals with LQT2 and 6 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 S654R around 48% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.844 0.997 -1 0.964 54
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 6 4 -
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.

S654R has 59 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
654 0
653 4
655 4
651 5 M651K,
657 6 G657V, G657S,
658 6
660 6 S660L,
650 6 L650X,
663 7
656 7 F656L, F656L, F656L,
659 8
652 8 Y652X,
664 9 Q664X,
649 9
659 9
648 9 G648A,
656 9 F656L, F656L, F656L,
553 9 L553V,
661 9 A661V,
657 10 G657V, G657S,
660 10 S660L,
647 10
662 11
667 11 Y667X,
557 11
661 11 A661V,
556 12
550 12
658 12
652 12 Y652X,
653 12
662 12
554 12
622 12 L622F,
554 12
666 12
560 13 I560fsX, I560M,
649 13
646 13
655 13
550 13
549 13 V549M,
623 14 T623I,
653 14
552 14 L552S,
650 14 L650X,
671 14 A671G, A671Del,
553 14 L553V,
665 14 R665Q,
670 14
555 15
663 15
668 15 S668L,
654 15
654 15
644 15 V644F, V644I,
547 15 A547T,
558 15 A558V, A558P, A558E,
624 15 S624R, S624R, S624R, S624N,