KCNH2 Variant V418D Detail

We estimate the penetrance of LQTS for KCNH2 V418D is 79%. We are unaware of any observations of this variant in individuals. V418D is not present in gnomAD. V418D 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 7 individuals with LQT2 and 3 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 V418D around 79% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.662 0.999 -3 0.946 81
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 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.

V418D has 61 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
418 0
419 4
417 5
421 5 T421fsX, T421M,
415 5
532 6
414 6 I414fsX,
531 6 R531Del, R531Q, R531W,
416 6
422 7 A422T,
420 7 Y420C,
535 8 V535M,
534 8 R534C,
463 8 F463L, F463L, F463L,
529 9
459 9
413 9 L413P,
423 9
533 9
528 10 R528P, R528W, R528X,
530 10
559 10 L559H, L559F,
425 10
424 11
411 11
462 11 M462Ins,
555 11
542 11
538 11
412 11 W412X,
504 11 A504V,
536 11 A536X,
552 11 L552S,
466 12 D466E, D466E,
460 12 D460fsX,
410 12 W410X,
556 12
456 12 D456Y,
501 12 D501H, D501N, D501Y,
563 12 W563X, W563C, W563G, W563C,
527 12
537 12 R537W,
551 13 F551L, F551L, F551L,
426 13 P426H,
458 13
539 13
562 13 H562P, H562Q, H562R, H562Q,
455 13
558 14 A558E, A558V, A558P,
505 14 A505V,
526 14
461 14
500 14 I500Del,
464 14 I464X,
465 14
409 14 V409L, V409M, V409L,
560 15 I560fsX, I560M,
503 15
525 15 K525N, K525N,
467 15
541 15 R541H, R541C,