KCNH2 Variant L401M Detail

We estimate the penetrance of LQTS for KCNH2 L401M is 67%. We are unaware of any observations of this variant in individuals. L401M is not present in gnomAD. L401M 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 6 individuals with LQT2 and 4 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L401M around 67% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.903 0.999 2 0.759 80
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 4 6 -
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.

L401M has 39 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
401 0
400 4 I400N,
404 5
403 5
402 5 H402R,
474 6 T474I,
473 7 T473P,
399 7
407 8
405 8
406 9
484 9
5 10
482 10 V482A,
483 10 V483I,
408 10
398 11 W398X, W398L,
472 11 R472X, R472C,
469 11
475 11 Y475C, Y475Del,
485 12 H485X,
476 12 V476I,
6 12 G6R,
470 12 N470D,
3 12
489 12 I489I, I489F,
541 13 R541H, R541C,
8 13
411 13
410 13 W410X,
481 13
409 13 V409L, V409L, V409M,
471 14 F471X,
486 14
4 14
7 14
695 15
466 15 D466E, D466E,
538 15