KCNH2 Variant S351L Detail

We estimate the penetrance of LQTS for KCNH2 S351L is 4%. This variant was found in a total of 6 carriers in 2 papers or gnomAD, 0 had LQTS. S351L is present in 4 alleles in gnomAD. S351L 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 S351L around 4% (0/16).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.466 0.354 1 0.601 0
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
Italy Cohort 2020 1 1 0
France Cohort 2020 1 1 0
LITERATURE, COHORT, AND GNOMAD: - 6 6 0 -
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.

S351L 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
351 0 S351L,
350 4
352 4
349 5
353 5 T353S, T353S,
348 7
354 7
347 8 P347S,
355 8 D355G,
346 8 D346Y, D346E, D346E, D346N,
356 8 R356H, R356C,
345 9 G345S,
357 9 E357D, E357D,
344 10
358 10
343 11 L343fsX,
359 11 I359V,
342 11 D342X, D342V, D342A,
360 11
341 12
361 12
340 13 F340L, F340L, F340L,
362 13
339 13
363 13 I363X,
338 14
364 14 K364X,
337 14 T337X, T337S, T337S,
365 14 E365G,
336 15
366 15 R366X, R366Q,