KCNH2 Variant V659M Detail

We estimate the penetrance of LQTS for KCNH2 V659M is 26%. We are unaware of any observations of this variant in individuals. V659M is not present in gnomAD. V659M 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 V659M around 26% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.905 0.998 1 0.952 38
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.

V659M has 53 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
659 0
660 4 S660L,
658 5
662 5
657 5 G657V, G657S,
656 5 F656L, F656L, F656L,
661 6 A661V,
663 6
550 6
655 7
553 7 L553V,
650 7 L650X,
653 8
654 8
554 8
549 9 V549M,
664 9 Q664X,
654 9
649 10
665 10 R665Q,
653 10
652 10 Y652X,
547 10 A547T,
666 10
546 10
657 11 G657V, G657S,
552 11 L552S,
557 11
651 11 M651K,
548 11
651 12 M651K,
551 12 F551L, F551L, F551L,
667 12 Y667X,
556 12
658 12
648 12 G648A,
655 12
660 12 S660L,
664 12 Q664X,
555 12
646 12
652 13 Y652X,
647 13
663 14
656 14 F656L, F656L, F656L,
543 14 S543fsX,
671 14 A671Del, A671G,
668 14 S668L,
674 14 H674fsX, H674Y,
650 15 L650X,
558 15 A558V, A558P, A558E,
623 15 T623I,
661 15 A661V,