KCNH2 Variant A527V Detail

We estimate the penetrance of LQTS for KCNH2 A527V is 37%. We are unaware of any observations of this variant in individuals. A527V is not present in gnomAD. A527V 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 3 individuals with LQT2 and 7 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 A527V around 37% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.834 0.994 0 0.811 46
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)
15528201 Xeno -14.6 -14.0 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

A527V has 44 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
527 0
526 4
528 5 R528X, R528P, R528W,
530 5
529 5
504 6 A504V,
503 6
531 7 R531W, R531Del, R531Q,
524 7
525 7 K525N, K525N,
506 8 I506V,
425 9
505 9 A505V,
421 9 T421M, T421fsX,
523 9
500 9 I500Del,
502 10 M502I, M502I, M502I,
508 10
507 10 P507S, P507L,
501 10 D501H, D501N, D501Y,
522 10 G522E,
532 11
426 11 P426H,
422 11 A422T,
533 11
460 11 D460fsX,
463 11 F463L, F463L, F463L,
429 12 A429P, A429V,
418 12
534 12 R534C,
499 12
428 13 S428L, S428fsX, S428X,
456 13 D456Y,
459 13
563 13 W563C, W563X, W563G, W563C,
521 13
420 13 Y420C,
423 14
424 14
464 14 I464X,
498 14
417 14
430 15
419 15