KCNH2 Variant V535A Detail

We estimate the penetrance of LQTS for KCNH2 V535A is 12%. We are unaware of any observations of this variant in individuals. V535A is not present in gnomAD. We have tested the trafficking efficiency of this variant, 76% of WT with a standard error of 15%; in our analysis we used SE < 20% as 'high quality'. Approximately below 50% of WT is considered PS3 moderate and below 30% is PS3 strong. V535A has been functionally characterized in 1 papers. 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 V535A around 12% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.834 0.967 0 0.908 35
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.

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)
15528201 Xeno -23.8 11.8 None None

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)
15528201 Xeno None None None

V535A has 49 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
535 0 V535M,
536 4 A536X,
538 5
532 5
533 6
539 6
542 6
415 7
534 7 R534C,
537 7 R537W,
418 8
414 8 I414fsX,
411 9
552 9 L552S,
540 9 D540fsX,
412 10 W412X,
419 10
541 10 R541C, R541H,
531 11 R531Del, R531Q, R531W,
543 11 S543fsX,
497 11 W497L, W497X,
417 11
530 11
556 11
416 11
501 11 D501N, D501H, D501Y,
555 12
421 12 T421fsX, T421M,
529 12
422 12 A422T,
463 12 F463L, F463L, F463L,
413 12 L413P,
549 12 V549M,
466 12 D466E, D466E,
551 12 F551L, F551L, F551L,
553 13 L553V,
500 13 I500Del,
548 13
410 13 W410X,
559 13 L559F, L559H,
407 13
408 13
544 14 E544A, E544fsX,
3 14
470 14 N470D,
504 14 A504V,
409 14 V409L, V409L, V409M,
563 15 W563C, W563X, W563C, W563G,
420 15 Y420C,