KCNH2 Variant R326C Detail

We estimate the penetrance of LQTS for KCNH2 R326C is 11%. This variant was found in a total of 3 carriers in 0 papers or gnomAD, 0 had LQTS. R326C is present in 3 alleles in gnomAD. R326C has not been functionally characterized. 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 R326C around 11% (1/13).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.147 1.0 -4 0.576 5
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: - 3 3 0 -
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.

R326C 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
326 0 R326H, R326fsX, R326C,
325 4 V325M,
327 4 Y327H,
324 5 L324L,
328 5 R328H, R328C, R328fsX,
323 7 D323E, D323N, D323E,
329 7
322 8
330 8 I330V,
321 8 D321Y,
331 8 S331T, S331N,
320 9 S320L, S320W, S320X,
332 9
319 10 T319T,
333 10
318 11
334 11 P334L,
317 11 N317S,
335 11 Q335X,
316 12
336 12
315 13
337 13 T337S, T337S, T337X,
314 13 G314S,
338 13
313 14
339 14
312 14 R312H, R312Del, R312C,
340 14 F340L, F340L, F340L,
311 15 L311R,
341 15