KCNH2 Variant V680L Detail

We estimate the penetrance of LQTS for KCNH2 V680L is 11%. We are unaware of any observations of this variant in individuals. V680L is not present in gnomAD. V680L 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 V680L around 11% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.917 0.887 1 0.76 14
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.

V680L has 61 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
680 0
677 5 M677T,
683 6
681 6 R681W,
684 6
679 6 R679Q, R679W,
678 7
682 7 E682X,
697 7 L697X,
676 7 Q676fsX, Q676X,
716 7 V716G,
701 7
698 8 E698X, E698K,
694 9 R694H, R694C,
685 9 R685H, R685P, R685C,
720 9
675 10
689 10
711 10 I711V,
673 10
717 10 L717P,
713 10 M713V,
687 11
702 11
686 11
715 11 A715A, A715T, A715sp, A715V,
719 11
674 11 H674Y, H674fsX,
700 11
693 11 L693X,
728 12
712 12 D712N,
699 12 E699D, E699D,
544 13 E544A, E544fsX,
709 13
724 13 L724X,
710 13
688 13
705 13 W705fsX, W705X,
695 13
704 13 A704T, A704V,
690 13
696 13 R696C, R696H,
718 13
708 13
714 13
725 14 Q725R, Q725fsX,
665 14 R665Q,
672 14 R672H, R672C,
721 14 P721L,
3 14
731 14 H731R,
691 14
545 15
727 15
732 15
5 15
668 15 S668L,
671 15 A671G, A671Del,
4 15
710 15