KCNH2 Variant S543G Detail

We estimate the penetrance of LQTS for KCNH2 S543G is 27%. We are unaware of any observations of this variant in individuals. S543G is not present in gnomAD. S543G 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 2 individuals with LQT2 and 8 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 S543G around 27% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
None None None None 33
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)
24407947 Xeno -12.6 None 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)
24407947 Xeno None None None

S543G 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
543 0 S543fsX,
540 5 D540fsX,
544 5 E544fsX, E544A,
539 6
549 6 V549M,
542 6
674 7 H674fsX, H674Y,
548 7
546 7
545 7
541 8 R541C, R541H,
552 9 L552S,
3 9
547 9 A547T,
673 10
670 10
412 10 W412X,
665 10 R665Q,
677 11 M677T,
538 11
535 11 V535M,
662 11
536 11 A536X,
553 11 L553V,
550 11
681 11 R681W,
678 11
671 11 A671Del, A671G,
551 12 F551L, F551L, F551L,
675 12
411 12
415 12
658 13
408 13
666 13
4 13
669 13 G669C, G669X, G669R,
702 13
667 14 Y667X,
537 14 R537W,
659 14
661 14 A661V,
555 14
556 14
705 15 W705fsX, W705X,
676 15 Q676X, Q676fsX,
698 15 E698X, E698K,
672 15 R672C, R672H,
655 15