KCNH2 Variant G496A Detail

We estimate the penetrance of LQTS for KCNH2 G496A is 73%. We are unaware of any observations of this variant in individuals. G496A is not present in gnomAD. G496A 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 G496A around 73% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.56 0.995 0 0.945 81
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.

G496A has 30 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
496 0
497 5 W497L, W497X,
495 5 K495X,
499 6
493 7 Y493C, Y493F, Y493H, Y493Ins,
498 7
492 7 H492Y,
494 7 F494Del,
500 8 I500Del,
501 9 D501N, D501Y, D501H,
537 9 R537W,
491 10 V491I,
490 11 A490T, A490P,
502 11 M502I, M502I, M502I,
533 11
470 12 N470D,
534 12 R534C,
489 12 I489F, I489I,
471 12 F471X,
475 12 Y475Del, Y475C,
467 13
503 13
530 13
536 13 A536X,
538 13
504 14 A504V,
477 14
466 14 D466E, D466E,
476 15 V476I,
473 15 T473P,