KCNH2 Variant A422D Detail

We estimate the penetrance of LQTS for KCNH2 A422D is 80%. We are unaware of any observations of this variant in individuals. A422D is not present in gnomAD. A422D 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 8 individuals with LQT2 and 2 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 A422D around 80% (8/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.71 0.997 -2 0.908 86
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 2 8 -
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.

A422D 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
422 0 A422T,
423 4
421 4 T421fsX, T421M,
419 6
425 6
559 6 L559H, L559F,
563 6 W563C, W563G, W563C, W563X,
529 6
426 6 P426H,
418 7
420 7 Y420C,
424 7
562 7 H562Q, H562P, H562R, H562Q,
532 8
531 9 R531W, R531Q, R531Del,
528 9 R528W, R528X, R528P,
417 10
558 10 A558P, A558V, A558E,
555 10
556 10
560 10 I560M, I560fsX,
526 10
427 10 Y427C, Y427S, Y427H,
428 11 S428fsX, S428L, S428X,
566 11 C566S, C566G, C566S, C566F, C566R,
416 11
530 11
415 11
527 11
561 11 A561T, A561V, A561P,
429 12 A429P, A429V,
456 12 D456Y,
459 12
535 12 V535M,
525 12 K525N, K525N,
533 12
564 12 L564L,
565 12
463 13 F463L, F463L, F463L,
414 13 I414fsX,
430 13
552 13 L552S,
534 13 R534C,
611 13 Y611D,
504 13 A504V,
567 13 I567T, I567M,
557 14
460 14 D460fsX,
431 14 F431L, F431L, F431L,
452 14
615 14 L615V, L615F,
551 14 F551L, F551L, F551L,
455 14
536 15 A536X,
413 15 L413P,