KCNQ1 Variant R380G Detail

We estimate the penetrance of LQTS for KCNQ1 R380G is 74%. This variant was found in a total of 1 carriers in 1 papers or gnomAD, 1 had LQTS. R380G is not present in gnomAD. R380G 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 7 individuals with LQT1 and 3 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 R380G around 74% (8/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.74 0.999 -1 0.891 78
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
26496715 2016 1 None 1 None
LITERATURE, COHORT, AND GNOMAD: - 1 0 1
VARIANT FEATURES ALONE: - 10 3 7 -
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.

R380G has 41 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
380 0 R380S, R380S, R380G,
377 4
518 5 R518Q, R518G,
376 6
381 6 C381Y,
379 6 W379R, W379R, W379C, W379C, W379G,
378 6 A378T,
521 7
391 7 T391A, T391I,
383 8
384 9
522 9 Y522S,
373 9 S373P,
375 9
517 9 I517T,
392 10 W392R, W392R, W392ins,
514 10 I514T,
374 10 L374H, L374F,
382 10
515 10
372 11
519 11 R519H, R519C,
525 11 A525T, A525V,
389 11 S389P,
390 11
394 11 I394L,
520 11 M520R,
393 12 K393N,
523 12
516 12
524 12 V524G,
385 12 E385K,
386 13 N386K, N386K,
371 13 A371T,
370 14 A370V,
513 14 T513A, T513S, T513S,
387 14 P387T,
526 14 K526Q, K526E,
512 14
511 14 R511Q, R511W,
528 15