KCNH2 Variant A490S Detail

We estimate the penetrance of LQTS for KCNH2 A490S is 60%. We are unaware of any observations of this variant in individuals. A490S is not present in gnomAD. A490S 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 5 individuals with LQT2 and 5 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 A490S around 60% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.778 0.997 1 0.935 71
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 5 5 -
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.

A490S has 32 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
490 0 A490P, A490T,
491 4 V491I,
489 4 I489F, I489I,
494 5 F494Del,
487 6 G487S, G487R,
493 6 Y493C, Y493H, Y493Ins, Y493F,
471 6 F471X,
492 7 H492Y,
486 7
488 9 R488H, R488C,
498 9
475 10 Y475Del, Y475C,
470 10 N470D,
472 10 R472X, R472C,
495 10 K495X,
473 10 T473P,
496 11
485 11 H485X,
483 11 V483I,
484 11
467 12
474 12 T474I,
468 12 L468F, L468R, L468X,
469 13
497 13 W497L, W497X,
477 13
499 13
501 14 D501H, D501Y, D501N,
476 14 V476I,
502 14 M502I, M502I, M502I,
466 15 D466E, D466E,
400 15 I400N,