KCNH2 Variant A504T Detail

We estimate the penetrance of LQTS for KCNH2 A504T is 40%. We are unaware of any observations of this variant in individuals. A504T is not present in gnomAD. A504T 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 3 individuals with LQT2 and 7 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 A504T around 40% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.74 0.992 0 0.952 49
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 7 3 -
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.

A504T has 51 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
504 0 A504V,
505 4 A505V,
503 4
531 5 R531W, R531Del, R531Q,
502 5 M502I, M502I, M502I,
506 6 I506V,
527 6
501 6 D501N, D501H, D501Y,
530 6
528 6 R528X, R528W, R528P,
463 7 F463L, F463L, F463L,
500 8 I500Del,
507 8 P507L, P507S,
460 8 D460fsX,
464 9 I464X,
534 9 R534C,
529 9
467 9
498 10
499 10
526 10
421 10 T421fsX, T421M,
533 10
466 10 D466E, D466E,
459 10
525 10 K525N, K525N,
508 10
532 11
524 11
418 11
461 11
462 12 M462Ins,
425 12
465 12
417 12
456 12 D456Y,
497 13 W497L, W497X,
414 13 I414fsX,
457 13 L457P,
422 13 A422T,
493 13 Y493Ins, Y493H, Y493C, Y493F,
470 13 N470D,
537 13 R537W,
468 13 L468X, L468R, L468F,
420 13 Y420C,
535 14 V535M,
496 14
458 14
523 15
522 15 G522E,
469 15