KCNH2 Variant P347S Detail

We estimate the penetrance of LQTS for KCNH2 P347S is 2%. This variant was found in a total of 298 carriers in 9 papers or gnomAD, 6 had LQTS. P347S is present in 281 alleles in gnomAD. P347S has been functionally characterized in 2 papers. This residue is located in a Non_Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 0 individuals with LQT2 and 10 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 P347S around 2% (6/308).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
None None None 0.545 1
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
Japan Cohort 2020 1 0 1
Italy Cohort 2020 2 2 0
France Cohort 2020 2 1 1
10973849 2000 1 0 1
12402336 2002 1 0 1
14661677 2003 1 1
17531263 2007 9 7 2
21410720 2011 1 0 VF at Cardiac Arrest
22378279 2012 1 0
LITERATURE, COHORT, AND GNOMAD: - 298 292 6 -
VARIANT FEATURES ALONE: - 10 10 0 -
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)
16432067 HEK293 112 None None None None
19673885 HEK293 -0.3 -1.4 1.019230769 1.037414966

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)
16432067 HEK293 None None None
19673885 HEK293 None None None

P347S has 31 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
347 0 P347S,
346 4 D346Y, D346E, D346N, D346E,
348 4
345 5 G345S,
349 5
344 7
350 7
343 8 L343fsX,
351 8 S351L,
342 8 D342V, D342A, D342X,
352 8
341 9
353 9 T353S, T353S,
340 10 F340L, F340L, F340L,
354 10
339 11
355 11 D355G,
338 11
356 11 R356H, R356C,
337 12 T337X, T337S, T337S,
357 12 E357D, E357D,
336 13
358 13
335 13 Q335X,
359 13 I359V,
334 14 P334L,
360 14
333 14
361 14
332 15
362 15