KCNH2 Variant L602R Detail

We estimate the penetrance of LQTS for KCNH2 L602R is 69%. We are unaware of any observations of this variant in individuals. L602R is not present in gnomAD. L602R 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 6 individuals with LQT2 and 4 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L602R around 69% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.339 0.001 0 0.632 77
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 4 6 -
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.

L602R has 31 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
602 0 L602X,
601 4 G601S,
603 4 G603D,
600 5
604 5 G604C, G604D, G604S,
599 7 S599N,
605 7 P605L,
598 8
606 8 S606Del, S606P, S606F,
597 8 Y597C, Y597H,
607 8
596 9 P596T, P596L, P596S, P596R,
608 9
595 10 K595N, K595N, K595E,
609 10 D609N, D609G,
594 11
610 11
593 11 I593R, I593V, I593T, I593X, I593K,
611 11 Y611D,
592 12 Q592X,
612 12 V612L, V612A, V612L,
591 13 D591H, D591N,
613 13 T613A, T613K, T613M, T613L,
590 13 G590V, G590D,
614 13 A614V, A614T,
589 14 L589P,
615 14 L615V, L615F,
588 14 N588K, N588K, N588D,
616 14 Y616S,
587 15
617 15 F617V, F617L, F617L, F617L,