KCNQ1 Variant A378V Detail

We estimate the penetrance of LQTS for KCNQ1 A378V is 30%. We are unaware of any observations of this variant in individuals. A378V is not present in gnomAD. A378V has not been functionally characterized. This residue is located in a Mild_Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 2 individuals with LQT1 and 8 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 A378V around 30% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
0.05 0.475 0 0.591 36
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 LQT1 Other Disease
LITERATURE, COHORT, AND GNOMAD: - 0 0 0
VARIANT FEATURES ALONE: - 10 8 2 -
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.

A378V has 38 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. This results from the fact that the functional KV7.1 channel 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 A378T,
377 4
381 5 C381Y,
522 6 Y522S,
375 6
379 6 W379R, W379R, W379C, W379C, W379G,
374 6 L374H, L374F,
380 6 R380S, R380S, R380G,
376 7
382 7
383 8
373 9 S373P,
518 9 R518Q, R518G,
525 9 A525T, A525V,
521 10
372 10
384 10
519 10 R519H, R519C,
523 10
526 10 K526Q, K526E,
371 11 A371T,
385 11 E385K,
391 11 T391A, T391I,
515 12
524 12 V524G,
370 12 A370V,
529 12
520 13 M520R,
517 13 I517T,
386 13 N386K, N386K,
516 13
392 14 W392R, W392R, W392ins,
389 14 S389P,
514 14 I514T,
528 14
390 15
369 15
530 15