KCNH2 Variant N470I Detail

We estimate the penetrance of LQTS for KCNH2 N470I is 85%. We are unaware of any observations of this variant in individuals. N470I is not present in gnomAD. N470I 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 8 individuals with LQT2 and 2 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 N470I around 85% (8/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-8.073 0.999 -4 0.944 89
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 2 8 -
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.

N470I 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
470 0 N470D,
469 5
471 5 F471X,
473 5 T473P,
466 5 D466E, D466E,
467 6
493 6 Y493C, Y493H, Y493Ins, Y493F,
468 7 L468F, L468R, L468X,
472 9 R472X, R472C,
489 9 I489I, I489F,
474 9 T474I,
407 9
465 9
498 9
534 9 R534C,
501 9 D501Y, D501N, D501H,
537 9 R537W,
400 10 I400N,
490 10 A490P, A490T,
475 10 Y475Del, Y475C,
538 10
410 10 W410X,
492 10 H492Y,
411 11
497 11 W497L, W497X,
464 11 I464X,
463 11 F463L, F463L, F463L,
402 11 H402R,
494 11 F494Del,
414 11 I414fsX,
496 12
502 12 M502I, M502I, M502I,
401 12
486 12
406 12
462 12 M462Ins,
399 13
491 13 V491I,
500 13 I500Del,
483 13 V483I,
505 13 A505V,
484 13
408 13
476 13 V476I,
533 13
404 13
504 13 A504V,
499 13
541 14 R541C, R541H,
398 14 W398X, W398L,
487 14 G487S, G487R,
531 14 R531W, R531Del, R531Q,
535 14 V535M,
485 14 H485X,
536 15 A536X,
413 15 L413P,
461 15
403 15
503 15
409 15 V409M, V409L, V409L,
488 15 R488H, R488C,