KCNH2 Variant D540A Detail

We estimate the penetrance of LQTS for KCNH2 D540A is 21%. We are unaware of any observations of this variant in individuals. D540A is not present in gnomAD. D540A has been functionally characterized in 3 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 2 individuals with LQT2 and 8 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 D540A around 21% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.668 0.965 -2 0.911 23
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 8 2 -
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)
9882738 Xeno 27 None None None 0.083333333
15528201 Xeno 12.7 -4.4 None None
27317659 HEK293 0.8 None None 0.145702306

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)
9882738 Xeno None None None
15528201 Xeno None None None
27317659 HEK293 None None None

D540A has 52 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
540 0 D540fsX,
539 4
543 5 S543fsX,
541 5 R541H, R541C,
3 6
542 6
544 7 E544fsX, E544A,
538 7
536 9 A536X,
535 9 V535M,
4 9
674 9 H674fsX, H674Y,
537 10 R537W,
673 10
411 10
545 11
549 11 V549M,
412 11 W412X,
670 11
702 11
408 11
548 11
677 12 M677T,
402 12 H402R,
552 12 L552S,
546 12
476 12 V476I,
407 13
415 13
681 13 R681W,
5 13
698 13 E698X, E698K,
671 13 A671Del, A671G,
705 14 W705X, W705fsX,
534 14 R534C,
533 14
403 14
414 14 I414fsX,
669 14 G669R, G669C, G669X,
547 14 A547T,
678 14
497 14 W497X, W497L,
409 14 V409L, V409L, V409M,
667 14 Y667X,
701 14
404 15
553 15 L553V,
532 15
706 15 S706C, S706F,
665 15 R665Q,
675 15
6 15 G6R,