KCNH2 Variant A505T Detail

We estimate the penetrance of LQTS for KCNH2 A505T is 20%. We are unaware of any observations of this variant in individuals. A505T is not present in gnomAD. A505T has not been functionally characterized. This residue is located in a Mild_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 A505T around 20% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.773 0.953 0 0.89 26
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.

A505T has 47 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
505 0 A505V,
504 4 A504V,
506 4 I506V,
502 5 M502I, M502I, M502I,
503 6
464 6 I464X,
507 6 P507S, P507L,
463 7 F463L, F463L, F463L,
460 7 D460fsX,
501 8 D501H, D501N, D501Y,
531 8 R531Del, R531W, R531Q,
467 8
528 9 R528W, R528X, R528P,
527 9
461 9
508 9
498 10
530 10
466 10 D466E, D466E,
500 10 I500Del,
465 10
459 10
534 11 R534C,
462 11 M462Ins,
499 11
468 11 L468R, L468X, L468F,
457 12 L457P,
525 12 K525N, K525N,
524 12
456 12 D456Y,
529 13
421 13 T421fsX, T421M,
526 13
470 13 N470D,
493 13 Y493C, Y493F, Y493H, Y493Ins,
458 13
533 13
417 13
418 14
471 14 F471X,
469 14
414 14 I414fsX,
532 14
425 14
509 14 D509N,
497 15 W497X, W497L,
494 15 F494Del,