KCNH2 Variant K407D Detail

We estimate the penetrance of LQTS for KCNH2 K407D is 37%. We are unaware of any observations of this variant in individuals. K407D is not present in gnomAD. K407D has been functionally characterized in 1 papers. 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 3 individuals with LQT2 and 7 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 K407D around 37% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
None None None None 43
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
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.

Functional Data Homozygously Collected

Steady state (S.S.) and peak tail current are relative % to wildtype (100% being no different from wildtype). V0.5 act/inact are the voltages at which half of the maximal current is reached during an activation and inactivation protocol, each is in units of mV and relative to wildtype. Recovery from inactivation (Rec. inact.) and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless).

PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Recov. Inact. Deactivation (%WT)
16550488 Xeno -43.08 None None None

Functional Data Heterozygously Collected

Functional parameters are the same as defined above.

PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Deactivation (%WT)
16550488 Xeno None None None

K407D has 47 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
407 0
408 5
411 5
406 5
410 6 W410X,
404 6
409 7 V409L, V409L, V409M,
405 7
402 7 H402R,
469 8
473 8 T473P,
541 8 R541C, R541H,
401 8
400 8 I400N,
470 9 N470D,
538 9
466 9 D466E, D466E,
414 9 I414fsX,
474 9 T474I,
403 9
412 10 W412X,
413 10 L413P,
3 11
542 11
465 12
534 12 R534C,
537 12 R537W,
462 12 M462Ins,
415 12
399 12
540 13 D540fsX,
468 13 L468R, L468X, L468F,
472 13 R472C, R472X,
467 13
475 13 Y475Del, Y475C,
535 13 V535M,
471 13 F471X,
463 13 F463L, F463L, F463L,
5 14
476 14 V476I,
544 14 E544A, E544fsX,
417 14
493 14 Y493C, Y493H, Y493Ins, Y493F,
539 14
489 15 I489I, I489F,
416 15
398 15 W398X, W398L,