KCNQ1 Variant A532P Detail

We estimate the penetrance of LQTS for KCNQ1 A532P is 43%. We are unaware of any observations of this variant in individuals. A532P is not present in gnomAD. A532P 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 4 individuals with LQT1 and 6 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 A532P around 43% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.26 0.979 -1 0.941 48
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 6 4 -
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.

A532P has 30 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
532 0
367 5 Q367H, Q367H,
533 5 R533W, R533Q,
529 6
530 7
370 7 A370V,
528 8
535 8
371 9 A371T,
369 9
368 9
364 10 F364L, F364L, F364L, F364S,
531 10
525 10 A525T, A525V,
365 10 N365H,
526 11 K526Q, K526E,
534 11
374 12 L374H, L374F,
373 12 S373P,
372 12
524 12 V524G,
540 13
539 13 R539W, R539L, R539Q,
527 13
544 13 Q544E,
357 14 Q357H, Q357H,
543 14 E543K,
375 14
358 15 K358T,
536 15