KCNH2 Variant H402L Detail

We estimate the penetrance of LQTS for KCNH2 H402L is 25%. We are unaware of any observations of this variant in individuals. H402L is not present in gnomAD. We have tested the trafficking efficiency of this variant, 0% of WT with a standard error of 0%; 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. H402L 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 H402L around 25% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-10.436 0.996 -3 0.913 86
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.

H402L has 51 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
402 0 H402R,
403 5
474 5 T474I,
401 5
404 7
476 7 V476I,
5 7
3 7
473 7 T473P,
407 7
475 8 Y475C, Y475Del,
400 9 I400N,
6 9 G6R,
541 9 R541C, R541H,
482 9 V482A,
4 9
408 9
483 9 V483I,
405 10
481 10
484 11
411 11
538 11
470 11 N470D,
406 11
540 12 D540fsX,
399 12
469 12
477 12
489 12 I489I, I489F,
480 12 E480V,
8 12
537 13 R537W,
7 13
409 13 V409L, V409M, V409L,
410 13 W410X,
695 13
472 13 R472X, R472C,
492 13 H492Y,
698 13 E698X, E698K,
544 13 E544A, E544fsX,
702 14
699 14 E699D, E699D,
542 14
478 14 A478D,
485 14 H485X,
471 14 F471X,
466 14 D466E, D466E,
493 14 Y493C, Y493Ins, Y493H, Y493F,
412 15 W412X,
539 15