KCNQ1 Variant A371S Detail

We estimate the penetrance of LQTS for KCNQ1 A371S is 65%. We are unaware of any observations of this variant in individuals. A371S is not present in gnomAD. A371S 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 6 individuals with LQT1 and 4 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 A371S around 65% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.82 0.999 -1 0.855 70
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 4 6 -
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.

A371S has 34 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
371 0 A371T,
372 4
370 4 A370V,
374 5 L374H, L374F,
373 5 S373P,
529 5
369 6
375 6
368 6
367 7 Q367H, Q367H,
525 8 A525T, A525V,
376 8
532 9
528 9
377 10
533 10 R533W, R533Q,
526 10 K526Q, K526E,
530 10
378 11 A378T,
522 11 Y522S,
365 11 N365H,
364 11 F364L, F364L, F364L, F364S,
524 12 V524G,
366 12 R366W, R366Q,
527 12
531 12
380 13 R380S, R380S, R380G,
521 13
362 13 K362R, K362del,
534 14
363 14 H363N,
379 14 W379R, W379R, W379C, W379C, W379G,
523 14
381 15 C381Y,