KCNH2 Variant M462L Detail

We estimate the penetrance of LQTS for KCNH2 M462L is 36%. We are unaware of any observations of this variant in individuals. M462L is not present in gnomAD. M462L 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 3 individuals with LQT2 and 7 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 M462L around 36% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.397 0.091 2 0.745 50
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 7 3 -
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.

M462L has 44 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
462 0 M462Ins,
461 5
465 5
463 6 F463L, F463L, F463L,
459 6
458 7
466 7 D466E, D466E,
464 7 I464X,
417 7
410 7 W410X,
460 8 D460fsX,
414 8 I414fsX,
413 8 L413P,
469 10
467 10
457 10 L457P,
531 10 R531Q, R531Del, R531W,
468 10 L468X, L468R, L468F,
418 11
456 11 D456Y,
416 11
505 11 A505V,
455 11
534 11 R534C,
411 11
420 12 Y420C,
504 12 A504V,
421 12 T421M, T421fsX,
415 12
470 12 N470D,
407 12
406 12
528 13 R528X, R528W, R528P,
409 13 V409M, V409L, V409L,
501 13 D501Y, D501H, D501N,
454 13
419 14
507 14 P507S, P507L,
502 14 M502I, M502I, M502I,
412 14 W412X,
408 15
506 15 I506V,
538 15
453 15