KCNH2 Variant V533W Detail

We estimate the penetrance of LQTS for KCNH2 V533W is 78%. We are unaware of any observations of this variant in individuals. V533W is not present in gnomAD. V533W has been functionally characterized in 1 papers. 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 V533W around 78% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
None None None None 72
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
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.

Functional Data Homozygously Collected

Steady state (S.S.) and peak tail current are relative % to wildtype (100% being no different from wildtype). V0.5 act/inact are the voltages at which half of the maximal current is reached during an activation and inactivation protocol, each is in units of mV and relative to wildtype. Recovery from inactivation (Rec. inact.) and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless).

PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Recov. Inact. Deactivation (%WT)
16166152 Xeno 3.9 None None 0.2

Functional Data Heterozygously Collected

Functional parameters are the same as defined above.

PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Deactivation (%WT)
16166152 Xeno None None None

V533W 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
533 0
532 5
534 5 R534C,
536 6 A536X,
535 6 V535M,
530 6
537 6 R537W,
500 7 I500Del,
497 7 W497L, W497X,
501 7 D501H, D501N, D501Y,
531 8 R531Del, R531W, R531Q,
538 8
529 9
418 9
504 10 A504V,
539 10
527 11
503 11
463 11 F463L, F463L, F463L,
414 11 I414fsX,
499 11
496 11
415 11
502 11 M502I, M502I, M502I,
421 12 T421fsX, T421M,
498 12
422 12 A422T,
542 12
466 12 D466E, D466E,
419 13
411 13
528 13 R528P, R528X, R528W,
417 13
493 13 Y493F, Y493C, Y493H, Y493Ins,
505 13 A505V,
470 13 N470D,
467 13
540 14 D540fsX,
526 14
552 14 L552S,
556 14
563 14 W563X, W563C, W563G, W563C,
559 14 L559F, L559H,
541 15 R541H, R541C,
425 15