KCNH2 Variant L666R Detail

We estimate the penetrance of LQTS for KCNH2 L666R is 12%. We are unaware of any observations of this variant in individuals. L666R is not present in gnomAD. L666R 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 L666R around 12% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.815 1.0 -2 0.958 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: - 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.

L666R 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
666 0
667 4 Y667X,
663 6
665 6 R665Q,
546 6
662 6
668 7 S668L,
547 7 A547T,
664 8 Q664X,
661 9 A661V,
669 9 G669R, G669C, G669X,
670 9
550 10
678 10
549 10 V549M,
659 10
671 10 A671Del, A671G,
548 11
660 11 S660L,
545 11
682 11 E682X,
672 12 R672C, R672H,
675 12
674 12 H674Y, H674fsX,
654 12
658 13
681 13 R681W,
709 13
543 13 S543fsX,
658 13
544 13 E544fsX, E544A,
685 14 R685C, R685H, R685P,
710 14
553 14 L553V,
657 14 G657V, G657S,
679 14 R679Q, R679W,
650 14 L650X,
551 14 F551L, F551L, F551L,
677 14 M677T,
671 15 A671Del, A671G,
705 15 W705fsX, W705X,
673 15
657 15 G657V, G657S,
674 15 H674Y, H674fsX,