KCNH2 Variant W410R Detail

We estimate the penetrance of LQTS for KCNH2 W410R is 43%. We are unaware of any observations of this variant in individuals. W410R is not present in gnomAD. W410R 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 4 individuals with LQT2 and 6 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 W410R around 43% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-13.323 1.0 -3 0.982 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 6 4 -
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.

W410R has 45 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
410 0 W410X,
413 5 L413P,
411 5
414 6 I414fsX,
407 6
409 6 V409M, V409L, V409L,
406 6
466 7 D466E, D466E,
462 7 M462Ins,
408 7
469 8
465 8
412 9 W412X,
417 9
463 10 F463L, F463L, F463L,
415 10
470 10 N470D,
405 10
416 10
534 10 R534C,
538 11
404 11
541 11 R541C, R541H,
473 11 T473P,
467 12
400 12 I400N,
418 12
468 12 L468X, L468R, L468F,
542 12
459 12
461 12
464 12 I464X,
535 13 V535M,
401 13
402 13 H402R,
537 13 R537W,
458 13
531 13 R531W, R531Del, R531Q,
474 14 T474I,
501 14 D501N, D501Y, D501H,
419 14
460 14 D460fsX,
471 14 F471X,
472 15 R472X, R472C,
403 15