KCNH2 Variant R328C Detail

We estimate the penetrance of LQTS for KCNH2 R328C is 5%. This variant was found in a total of 171 carriers in 8 papers or gnomAD, 8 had LQTS. R328C is present in 161 alleles in gnomAD. R328C 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 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 R328C around 5% (9/181).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.057 1.0 -4 0.77 4
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
France Cohort 2020 1 1 0
23098067 2012 1 0 1
16253915 2005 2 1 1
15840476 2005 2 0 2
16922724 2006 3 0 3
24217263 2013 1 0 congenital LQT
29650123 2018 1 0
LITERATURE, COHORT, AND GNOMAD: - 171 163 8 -
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)
16253915 Xeno 150 None None None None
16432067 HEK293 85 None 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)
16253915 Xeno 45 67 None None None
16432067 HEK293 None None None

R328C 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
328 0 R328fsX, R328H, R328C,
327 4 Y327H,
329 4
326 5 R326H, R326fsX, R326C,
330 5 I330V,
325 7 V325M,
331 7 S331T, S331N,
324 8 L324L,
332 8
323 8 D323N, D323E, D323E,
333 8
322 9
334 9 P334L,
321 10 D321Y,
335 10 Q335X,
320 11 S320W, S320L, S320X,
336 11
319 11 T319T,
337 11 T337X, T337S, T337S,
318 12
338 12
317 13 N317S,
339 13
316 13
340 13 F340L, F340L, F340L,
315 14
341 14
314 14 G314S,
342 14 D342A, D342X, D342V,
313 15
343 15 L343fsX,