KCNH2 Variant I467M Detail

We estimate the penetrance of LQTS for KCNH2 I467M is 53%. We are unaware of any observations of this variant in individuals. I467M is not present in gnomAD. I467M 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 5 individuals with LQT2 and 5 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 I467M around 53% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.78 1.0 1 0.831 64
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 5 5 -
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.

I467M has 49 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
467 0
468 5 L468R, L468X, L468F,
466 5 D466E, D466E,
470 6 N470D,
464 6 I464X,
465 6
471 6 F471X,
469 7
498 7
501 7 D501N, D501H, D501Y,
493 7 Y493H, Y493C, Y493Ins, Y493F,
502 8 M502I, M502I, M502I,
463 8 F463L, F463L, F463L,
505 8 A505V,
534 9 R534C,
504 9 A504V,
462 10 M462Ins,
473 10 T473P,
461 11
472 11 R472X, R472C,
494 11 F494Del,
503 11
531 11 R531Q, R531Del, R531W,
500 11 I500Del,
506 11 I506V,
410 12 W410X,
490 12 A490T, A490P,
499 12
460 12 D460fsX,
414 12 I414fsX,
537 12 R537W,
497 12 W497L, W497X,
489 12 I489F, I489I,
496 13
407 13
459 13
538 13
507 13 P507L, P507S,
533 13
530 13
411 14
492 14 H492Y,
400 14 I400N,
417 14
474 14 T474I,
486 14
528 15 R528X, R528W, R528P,
491 15 V491I,
418 15