KCNH2 Variant M502I Detail

We estimate the penetrance of LQTS for KCNH2 M502I is 12%. This variant was found in a total of 2 carriers in 0 papers or gnomAD, 0 had LQTS. M502I is present in 2 alleles in gnomAD. M502I has not been functionally characterized. This residue is located in a Mild_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 M502I around 12% (1/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.798 0.004 1 0.605 19
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: - 2 2 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.

M502I has 42 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
502 0 M502I, M502I, M502I,
503 4
501 5 D501H, D501Y, D501N,
505 5 A505V,
504 5 A504V,
498 5
499 6
500 6 I500Del,
506 6 I506V,
467 8
530 9
464 9 I464X,
531 9 R531Del, R531Q, R531W,
527 10
493 10 Y493H, Y493C, Y493Ins, Y493F,
463 10 F463L, F463L, F463L,
534 10 R534C,
507 10 P507L, P507S,
496 11
494 11 F494Del,
466 11 D466E, D466E,
497 11 W497X, W497L,
533 11
528 12 R528P, R528W, R528X,
470 12 N470D,
468 12 L468X, L468F, L468R,
460 12 D460fsX,
471 12 F471X,
508 12
465 13
537 13 R537W,
529 13
495 13 K495X,
524 14
526 14
461 14
532 14
469 14
490 14 A490T, A490P,
462 14 M462Ins,
459 15
525 15 K525N, K525N,