KCNH2 Variant W412G Detail

We estimate the penetrance of LQTS for KCNH2 W412G is 19%. We are unaware of any observations of this variant in individuals. W412G is not present in gnomAD. W412G 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 W412G around 19% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-12.372 0.999 -3 0.92 17
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.

W412G has 42 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
412 0 W412X,
542 5
411 6
415 6
409 6 V409L, V409M, V409L,
408 7
413 7 L413P,
541 7 R541H, R541C,
414 8 I414fsX,
416 8
548 9
545 9
410 9 W410X,
544 10 E544fsX, E544A,
538 10
551 10 F551L, F551L, F551L,
407 10
535 10 V535M,
552 10 L552S,
543 10 S543fsX,
540 11 D540fsX,
539 11
417 11
418 11
549 11 V549M,
547 12 A547T,
419 12
405 12
406 12
546 12
3 12
404 13
555 13
534 13 R534C,
536 13 A536X,
550 14
537 14 R537W,
532 14
466 14 D466E, D466E,
462 14 M462Ins,
553 15 L553V,
402 15 H402R,