KCNH2 Variant W497G Detail

We estimate the penetrance of LQTS for KCNH2 W497G is 75%. We are unaware of any observations of this variant in individuals. W497G is not present in gnomAD. W497G 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 7 individuals with LQT2 and 3 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 W497G around 75% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-12.18 1.0 -3 0.922 76
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 3 7 -
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.

W497G has 39 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
497 0 W497X, W497L,
496 5
537 5 R537W,
500 7 I500Del,
501 7 D501H, D501Y, D501N,
533 7
493 8 Y493H, Y493Ins, Y493C, Y493F,
499 8
498 8
534 8 R534C,
536 9 A536X,
492 9 H492Y,
495 9 K495X,
538 9
530 11
470 11 N470D,
535 11 V535M,
502 11 M502I, M502I, M502I,
494 11 F494Del,
532 12
467 12
503 12
475 13 Y475Del, Y475C,
466 13 D466E, D466E,
539 13
504 13 A504V,
490 13 A490T, A490P,
531 13 R531Del, R531W, R531Q,
471 13 F471X,
491 13 V491I,
489 14 I489F, I489I,
476 14 V476I,
463 14 F463L, F463L, F463L,
540 14 D540fsX,
473 14 T473P,
411 15
477 15
505 15 A505V,
414 15 I414fsX,