KCNH2 Variant M713V Detail

We estimate the penetrance of LQTS for KCNH2 M713V is 11%. This variant was found in a total of 1 carriers in 0 papers or gnomAD, 0 had LQTS. M713V is present in 1 alleles in gnomAD. M713V 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 M713V around 11% (1/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.764 0.427 1 0.824 16
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: - 1 1 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.

M713V has 54 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
713 0 M713V,
714 5
712 5 D712N,
711 5 I711V,
683 6
716 6 V716G,
715 7 A715sp, A715A, A715T, A715V,
708 7
686 7
717 8 L717P,
687 8
710 9
707 9
760 9
679 9 R679W, R679Q,
709 10
682 10 E682X,
718 10
732 10
680 10
728 11
704 11 A704V, A704T,
684 11
729 11
759 11 K759N, K759N,
720 12
762 12
725 12 Q725fsX, Q725R,
719 12
705 12 W705fsX, W705X,
761 12
719 13
706 13 S706C, S706F,
689 13
731 13 H731R,
676 13 Q676fsX, Q676X,
685 13 R685P, R685C, R685H,
688 14
672 14 R672C, R672H,
678 14
756 14 M756V,
733 14
697 14 L697X,
703 14
700 15
831 15
726 15
755 15
681 15 R681W,
758 15
718 15
701 15
669 15 G669C, G669X, G669R,
724 15 L724X,