KCNH2 Variant V423L Detail

We estimate the penetrance of LQTS for KCNH2 V423L is 30%. We are unaware of any observations of this variant in individuals. V423L is not present in gnomAD. We have tested the trafficking efficiency of this variant, 0% of WT with a standard error of 6%; in our analysis we used SE < 20% as 'high quality'. Approximately below 50% of WT is considered PS3 moderate and below 30% is PS3 strong. V423L has not been functionally characterized. This residue is located in a Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 2 individuals with LQT2 and 8 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 V423L around 30% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.889 0.243 1 0.679 73
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 LQT2 Other Disease
LITERATURE, COHORT, AND GNOMAD: - 0 0 0 -
VARIANT FEATURES ALONE: - 10 8 2 -
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.

V423L has 56 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 since the functional KV11.1 channel (protein product of KCNH2/hERG) 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
423 0
422 4 A422T,
424 4
562 6 H562R, H562P, H562Q, H562Q,
420 6 Y420C,
426 6 P426H,
421 6 T421fsX, T421M,
425 6
419 6
559 7 L559F, L559H,
427 7 Y427S, Y427H, Y427C,
563 8 W563C, W563X, W563C, W563G,
418 9
558 9 A558E, A558V, A558P,
428 9 S428L, S428X, S428fsX,
566 10 C566S, C566S, C566G, C566F, C566R,
529 10
611 10 Y611D,
561 10 A561P, A561T, A561V,
555 11
417 11
528 11 R528W, R528P, R528X,
416 11
560 11 I560fsX, I560M,
565 11
429 11 A429P, A429V,
556 11
532 11
456 11 D456Y,
431 12 F431L, F431L, F431L,
452 12
430 12
615 12 L615V, L615F,
531 12 R531Del, R531Q, R531W,
526 12
564 12 L564L,
415 12
459 13
525 13 K525N, K525N,
455 13
567 13 I567M, I567T,
557 14
527 14
432 14
612 14 V612L, V612L, V612A,
614 14 A614T, A614V,
530 14
551 14 F551L, F551L, F551L,
619 14
552 14 L552S,
453 15
618 15 T618S, T618S,
414 15 I414fsX,
608 15
460 15 D460fsX,
569 15 Y569X, Y569H, Y569C,