KCNH2 Variant C555S Detail

We estimate the penetrance of LQTS for KCNH2 C555S is 19%. We are unaware of any observations of this variant in individuals. C555S is not present in gnomAD. We have tested the trafficking efficiency of this variant, 119% of WT with a standard error of 10%; 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. C555S 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 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 C555S around 19% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-9.218 0.973 -1 0.902 44
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.

C555S has 55 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
555 0
556 4
552 5 L552S,
551 5 F551L, F551L, F551L,
554 6
558 6 A558E, A558V, A558P,
559 6 L559F, L559H,
553 7 L553V,
419 7
557 7
550 9
560 9 I560M, I560fsX,
415 9
549 10 V549M,
548 10
422 10 A422T,
655 10
423 11
561 11 A561T, A561P, A561V,
416 11
418 11
646 11
562 11 H562R, H562Q, H562Q, H562P,
563 11 W563C, W563X, W563C, W563G,
532 11
535 12 V535M,
656 12 F656L, F656L, F656L,
542 12
547 12 A547T,
651 12 M651K,
659 12
619 12
421 13 T421fsX, T421M,
412 13 W412X,
650 13 L650X,
649 13
539 14
417 14
420 14 Y420C,
658 14
546 14
536 14 A536X,
615 14 L615V, L615F,
543 14 S543fsX,
622 14 L622F,
424 14
642 14 I642V, I642Del,
414 14 I414fsX,
564 15 L564L,
647 15
654 15
662 15
643 15
529 15
652 15 Y652X,