KCNH2 Variant R356H Detail

We estimate the penetrance of LQTS for KCNH2 R356H is 8%. This variant was found in a total of 16 carriers in 1 papers or gnomAD, 1 had LQTS. R356H is present in 15 alleles in gnomAD. R356H 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 0 individuals with LQT2 and 10 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 R356H around 8% (1/26).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.287 0.998 -2 0.531 2
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
24667783 2015 1 0 1
LITERATURE, COHORT, AND GNOMAD: - 16 15 1 -
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.

R356H 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
356 0 R356H, R356C,
355 4 D355G,
357 4 E357D, E357D,
354 5
358 5
353 7 T353S, T353S,
359 7 I359V,
352 8
360 8
351 8 S351L,
361 8
350 9
362 9
349 10
363 10 I363X,
348 11
364 11 K364X,
347 11 P347S,
365 11 E365G,
346 12 D346Y, D346E, D346N, D346E,
366 12 R366Q, R366X,
345 13 G345S,
367 13 T367S, T367S,
344 13
368 13 H368Y,
343 14 L343fsX,
369 14 N369K, N369K,
342 14 D342V, D342A, D342X,
370 14
341 15
371 15