KCNH2 Variant I506N Detail

We estimate the penetrance of LQTS for KCNH2 I506N is 24%. We are unaware of any observations of this variant in individuals. I506N is not present in gnomAD. I506N 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 2 individuals with LQT2 and 8 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 I506N around 24% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.512 0.962 -4 0.954 22
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 8 2 -
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.

I506N 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
506 0 I506V,
505 4 A505V,
507 4 P507L, P507S,
503 5
504 6 A504V,
508 6
502 6 M502I, M502I, M502I,
527 8
528 9 R528P, R528W, R528X,
460 9 D460fsX,
524 9
464 9 I464X,
531 10 R531W, R531Q, R531Del,
501 10 D501H, D501N, D501Y,
525 10 K525N, K525N,
463 11 F463L, F463L, F463L,
530 11
500 11 I500Del,
498 11
499 11
467 11
526 12
509 12 D509N,
510 12
461 12
457 13 L457P,
459 13
529 13
456 14 D456Y,
522 14 G522E,
465 14
466 14 D466E, D466E,
534 14 R534C,
523 14
521 14
421 14 T421fsX, T421M,
425 15
462 15 M462Ins,
468 15 L468R, L468X, L468F,