KCNQ1 Variant Q376H Detail

We estimate the penetrance of LQTS for KCNQ1 Q376H is 61%. We are unaware of any observations of this variant in individuals. Q376H is not present in gnomAD. Q376H 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 Q376H around 61% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.76 0.999 0 0.893 65
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.

Q376H 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
376 0
373 5 S373P,
375 5
372 5
377 5
380 6 R380S, R380S, R380G,
374 7 L374H, L374F,
378 7 A378T,
379 8 W379R, W379R, W379C, W379C, W379G,
371 8 A371T,
370 9 A370V,
525 9 A525T, A525V,
521 9
522 10 Y522S,
369 10
381 10 C381Y,
518 11 R518Q, R518G,
391 12 T391A, T391I,
368 12
383 12
524 12 V524G,
529 12
382 12
528 13
526 13 K526Q, K526E,
523 13
384 14
517 14 I517T,
390 14
519 15 R519H, R519C,
520 15 M520R,
367 15 Q367H, Q367H,