KCNH2 Variant V409M Detail

We estimate the penetrance of LQTS for KCNH2 V409M is 2%. This variant was found in a total of 27 carriers in 0 papers or gnomAD (version 4), 0 had LQTS. V409M is present in 27 alleles in gnomAD. We have tested the trafficking efficiency of this variant, 112% of WT with a standard error of 13%; 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. V409M has not been functionally characterized. This residue is located in a Non_Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 0 individuals with LQT2 and 10 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 V409M around 2% (0/37).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.756 0.997 1 0.879 3
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: - 27 16 0 -
VARIANT FEATURES ALONE: - 10 10 0 -
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.

V409M has 35 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
409 0 V409L, V409M, V409L,
408 4
412 6 W412X,
411 6
410 6 W410X,
406 7
405 7
413 7 L413P,
407 7
404 9
414 9 I414fsX,
541 9 R541H, R541C,
542 10
415 11
416 11
545 12
538 12
417 13
544 13 E544A, E544fsX,
462 13 M462Ins,
403 13
402 13 H402R,
466 13 D466E, D466E,
469 13
401 13
3 13
400 14 I400N,
548 14
540 14 D540fsX,
535 14 V535M,
418 14
473 15 T473P,
465 15
534 15 R534C,
470 15 N470D,