KCNH2 Variant T556P Detail

We estimate the penetrance of LQTS for KCNH2 T556P is 25%. We are unaware of any observations of this variant in individuals. T556P is not present in gnomAD. We have tested the trafficking efficiency of this variant, 0% of WT with a standard error of 11%; in our analysis we used SE < 20% as 'high quality'. Approximately below 50% of WT is considered PS3 moderate and below 30% is PS3 strong. T556P has not been functionally characterized. This residue is located in a Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 2 individuals with LQT2 and 8 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 T556P around 25% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.096 0.116 -1 0.932 61
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 8 2 -
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.

T556P 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
556 0
555 4
559 5 L559F, L559H,
558 6 A558E, A558V, A558P,
557 6
553 6 L553V,
560 6 I560M, I560fsX,
552 6 L552S,
554 7
655 8
551 8 F551L, F551L, F551L,
651 9 M651K,
561 9 A561T, A561V, A561P,
563 9 W563G, W563C, W563C, W563X,
419 9
550 10
422 10 A422T,
532 10
562 10 H562Q, H562Q, H562P, H562R,
656 10 F656L, F656L, F656L,
549 11 V549M,
535 11 V535M,
423 11
415 11
646 11
619 12
654 12
418 12
622 12 L622F,
659 12
548 12
658 12
564 12 L564L,
647 13
648 13 G648A,
652 13 Y652X,
536 13 A536X,
539 13
542 13
649 13
618 13 T618S, T618S,
421 13 T421fsX, T421M,
650 13 L650X,
650 13 L650X,
529 14
416 14
653 14
615 14 L615V, L615F,
657 14 G657V, G657S,
623 14 T623I,
533 14
547 14 A547T,
565 14
543 14 S543fsX,
662 15
426 15 P426H,
642 15 I642Del, I642V,
644 15 V644F, V644I,