KCNH2 Variant L552M Detail

We estimate the penetrance of LQTS for KCNH2 L552M is 18%. We are unaware of any observations of this variant in individuals. L552M is not present in gnomAD. L552M 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 L552M around 18% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.917 1.0 2 0.739 29
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.

L552M has 56 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
552 0 L552S,
551 5 F551L, F551L, F551L,
553 5 L553V,
555 5
549 6 V549M,
556 6
548 6
550 7
554 8
542 8
415 8
535 9 V535M,
543 9 S543fsX,
539 9
547 9 A547T,
419 10
412 10 W412X,
655 10
559 10 L559F, L559H,
546 10
558 11 A558V, A558P, A558E,
557 11
659 11
536 11 A536X,
532 11
418 11
416 11
658 11
662 12
545 12
560 12 I560M, I560fsX,
540 12 D540fsX,
656 12 F656L, F656L, F656L,
538 13
544 13 E544A, E544fsX,
422 13 A422T,
651 13 M651K,
541 13 R541C, R541H,
414 13 I414fsX,
411 13
654 14
533 14
657 14 G657S, G657V,
650 14 L650X,
417 14
646 14
665 14 R665Q,
563 14 W563C, W563C, W563G, W563X,
423 14
413 15 L413P,
663 15
661 15 A661V,
674 15 H674fsX, H674Y,
561 15 A561P, A561V, A561T,
421 15 T421M, T421fsX,
660 15 S660L,