KCNH2 Variant K407M Detail

We estimate the penetrance of LQTS for KCNH2 K407M is 20%. We are unaware of any observations of this variant in individuals. K407M is not present in gnomAD. We have tested the trafficking efficiency of this variant, 0% of WT with a standard error of %; 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. K407M 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 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 K407M around 20% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.71 1.0 -2 0.941 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
LITERATURE, COHORT, AND GNOMAD: - 0 0 0 -
VARIANT FEATURES ALONE: - 10 9 1 -
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.

K407M 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, V409M, V409L,
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 L468F, L468X, L468R,
472 13 R472X, R472C,
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, Y493F, Y493H, Y493Ins,
539 14
489 15 I489I, I489F,
416 15
398 15 W398L, W398X,