KCNH2 Variant F551Y Detail

We estimate the penetrance of LQTS for KCNH2 F551Y is 7%. We are unaware of any observations of this variant in individuals. F551Y is not present in gnomAD. F551Y 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 F551Y around 7% (0/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.412 0.236 2 0.737 4
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.

F551Y has 45 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
551 0 F551L, F551L, F551L,
552 5 L552S,
555 5
548 6
550 6
554 7
549 7 V549M,
553 7 L553V,
547 8 A547T,
556 8
415 9
419 10
412 10 W412X,
546 10
416 10
542 10
558 11 A558P, A558V, A558E,
559 11 L559F, L559H,
557 11
545 12
659 12
543 12 S543fsX,
662 12
535 12 V535M,
418 13
655 13
646 13
650 13 L650X,
539 13
656 13 F656L, F656L, F656L,
413 14 L413P,
544 14 E544fsX, E544A,
658 14
560 14 I560M, I560fsX,
663 14
414 14 I414fsX,
422 14 A422T,
417 14
532 14
423 14
666 14
411 15
647 15
541 15 R541H, R541C,
649 15