KCNH2 Variant L678M Detail

We estimate the penetrance of LQTS for KCNH2 L678M is 8%. We are unaware of any observations of this variant in individuals. L678M is not present in gnomAD. L678M 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 0 individuals with LQT2 and 10 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L678M around 8% (0/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.909 0.431 2 0.746 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 10 0 -
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.

L678M has 55 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
678 0
677 5 M677T,
681 5 R681W,
682 6 E682X,
675 6
679 6 R679W, R679Q,
680 7
674 7 H674fsX, H674Y,
665 7 R665Q,
676 7 Q676fsX, Q676X,
673 9
668 9 S668L,
685 9 R685P, R685H, R685C,
546 10
666 10
544 10 E544fsX, E544A,
684 10
711 10 I711V,
683 10
545 11
671 11 A671Del, A671G,
701 11
543 11 S543fsX,
709 11
669 11 G669X, G669R, G669C,
710 12
662 12
716 12 V716G,
698 12 E698K, E698X,
672 12 R672H, R672C,
672 12 R672H, R672C,
712 13 D712N,
547 13 A547T,
670 13
686 13
667 13 Y667X,
549 13 V549M,
702 13
661 13 A661V,
697 13 L697X,
694 13 R694C, R694H,
664 14 Q664X,
713 14 M713V,
708 14
669 14 G669X, G669R, G669C,
705 14 W705X, W705fsX,
715 14 A715A, A715sp, A715V, A715T,
548 14
540 14 D540fsX,
663 14
670 14
3 14
671 15 A671Del, A671G,
687 15
689 15