KCNQ1 Variant A372S Detail

We estimate the penetrance of LQTS for KCNQ1 A372S is 52%. We are unaware of any observations of this variant in individuals. A372S is not present in gnomAD. A372S has not been functionally characterized. This residue is located in a Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 5 individuals with LQT1 and 5 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 A372S around 52% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.62 1.0 1 0.864 60
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
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.

A372S has 32 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
372 0
371 4 A371T,
373 4 S373P,
375 5
376 5
370 5 A370V,
369 6
374 6 L374H, L374F,
368 7
377 8
525 8 A525T, A525V,
529 9
378 10 A378T,
367 10 Q367H, Q367H,
528 11
380 11 R380S, R380S, R380G,
522 11 Y522S,
379 12 W379R, W379R, W379C, W379C, W379G,
526 12 K526Q, K526E,
532 12
524 12 V524G,
521 12
365 12 N365H,
530 13
533 13 R533W, R533Q,
364 13 F364L, F364L, F364L, F364S,
381 14 C381Y,
366 14 R366W, R366Q,
527 14
523 14
518 15 R518Q, R518G,
531 15