KCNH2 Variant A661S Detail

We estimate the penetrance of LQTS for KCNH2 A661S is 11%. We are unaware of any observations of this variant in individuals. A661S is not present in gnomAD. A661S 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 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 A661S around 11% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.907 0.999 1 0.917 13
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 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.

A661S 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
661 0 A661V,
662 4
660 4 S660L,
664 5 Q664X,
663 6
659 6
658 6
657 6 G657V, G657S,
665 6 R665Q,
666 9
654 9
664 10 Q664X,
668 10 S668L,
657 10 G657V, G657S,
656 10 F656L, F656L, F656L,
550 10
653 10
667 10 Y667X,
671 10 A671Del, A671G,
549 10 V549M,
655 11
546 11
658 11
654 11
553 11 L553V,
675 11
660 12 S660L,
674 12 H674Y, H674fsX,
671 12 A671Del, A671G,
547 12 A547T,
650 12 L650X,
653 12
661 13 A661V,
661 13 A661V,
663 13
669 13 G669C, G669X, G669R,
678 13
670 13
670 13
548 13
655 13
554 13
660 14 S660L,
543 14 S543fsX,
672 14 R672H, R672C,
668 14 S668L,
652 14 Y652X,
657 14 G657V, G657S,
672 14 R672H, R672C,
649 14
667 14 Y667X,
651 15 M651K,
552 15 L552S,
656 15 F656L, F656L, F656L,
659 15
669 15 G669C, G669X, G669R,