KCNH2 Variant M756L Detail

We estimate the penetrance of LQTS for KCNH2 M756L is 8%. We are unaware of any observations of this variant in individuals. M756L is not present in gnomAD. M756L 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 M756L around 8% (0/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.358 0.02 2 0.664 8
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.

M756L has 58 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
756 0 M756V,
755 4
757 6
726 6
729 6
753 6 A753S,
725 6 Q725fsX, Q725R,
722 7
754 7
752 8 R752Q, R752P, R752W,
758 8
728 9
717 9 L717P,
730 9
759 9 K759N, K759N,
723 10 C723R, C723G, C723X,
733 10
837 10 D837N, D837Y, D837G,
727 10
751 10 L751V,
724 10 L724X,
721 10 P721L,
732 10
749 11
841 11 V841L, V841L,
714 11
750 11 C750X,
718 11
833 12
720 12
838 12 L838R,
840 12 E840Q,
760 12
774 13 D774X, D774Y,
737 13 L737P,
731 13 H731R,
775 13
834 13 H834R,
719 13
832 13
716 13 V716G,
771 13 H771fsX, H771R,
831 13
845 14
713 14 M713V,
715 14 A715sp, A715A, A715T, A715V,
748 14
736 14
844 14 M844V,
777 14
743 14
770 15
842 15
836 15
687 15
768 15
773 15
693 15 L693X,