KCNH2 Variant L378V Detail

We estimate the penetrance of LQTS for KCNH2 L378V is 8%. We are unaware of any observations of this variant in individuals. L378V is not present in gnomAD. L378V 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 L378V around 8% (0/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.855 0.931 1 0.859 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: - 0 0 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.

L378V 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
378 0
377 4
379 4 S379Y,
376 5 Q376sp, Q376R,
380 5 L380X,
375 7
381 7
374 8
382 8 A382T,
373 8
383 8
372 9
384 9
371 10
385 10
370 11
386 11 P386X,
369 11 N369K, N369K,
387 11
368 12 H368Y,
388 12
367 13 T367S, T367S,
389 13
366 13 R366Q, R366X,
390 13
365 14 E365G,
391 14 Q391X,
364 14 K364X,
392 14
363 15 I363X,
393 15 P393L,