KCNH2 Variant A408T Detail

We estimate the penetrance of LQTS for KCNH2 A408T is 10%. We are unaware of any observations of this variant in individuals. A408T is not present in gnomAD. A408T has not been functionally characterized. This residue is located in a Non_Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 0 individuals with LQT2 and 10 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 A408T around 10% (0/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.807 0.992 0 0.906 7
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 10 0 -
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.

A408T has 38 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
408 0
409 4 V409L, V409M, V409L,
407 5
411 5
405 6
541 6 R541H, R541C,
404 6
412 7 W412X,
406 7
410 7 W410X,
542 9
402 9 H402R,
413 9 L413P,
403 10
3 10
414 10 I414fsX,
538 10
544 10 E544fsX, E544A,
401 10
540 11 D540fsX,
545 11
415 11
400 12 I400N,
469 12
473 12 T473P,
466 13 D466E, D466E,
474 13 T474I,
543 13 S543fsX,
535 13 V535M,
539 13
470 13 N470D,
5 13
416 13
548 14
537 14 R537W,
534 14 R534C,
417 14
462 15 M462Ins,