KCNH2 Variant I469F Detail

We estimate the penetrance of LQTS for KCNH2 I469F is 25%. We are unaware of any observations of this variant in individuals. I469F is not present in gnomAD. We have tested the trafficking efficiency of this variant, 62% of WT with a standard error of 20%; 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. I469F 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 2 individuals with LQT2 and 8 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 I469F around 25% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.707 0.998 0 0.973 67
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.

I469F has 52 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
469 0
470 5 N470D,
468 5 L468X, L468R, L468F,
466 5 D466E, D466E,
473 6 T473P,
465 6
467 7
471 7 F471X,
472 7 R472X, R472C,
400 8 I400N,
407 8
410 8 W410X,
406 9
464 10 I464X,
462 10 M462Ins,
474 10 T474I,
493 10 Y493Ins, Y493F, Y493H, Y493C,
411 11
463 11 F463L, F463L, F463L,
399 11
401 11
414 11 I414fsX,
398 11 W398X, W398L,
534 11 R534C,
489 11 I489F, I489I,
402 12 H402R,
404 12
501 12 D501H, D501Y, D501N,
408 12
498 12
538 12
461 12
486 13
490 13 A490T, A490P,
413 13 L413P,
537 13 R537W,
409 13 V409L, V409L, V409M,
475 13 Y475C, Y475Del,
405 14
505 14 A505V,
484 14
502 14 M502I, M502I, M502I,
485 14 H485X,
492 14 H492Y,
541 15 R541C, R541H,
417 15
494 15 F494Del,
403 15
504 15 A504V,
531 15 R531Q, R531Del, R531W,
459 15
483 15 V483I,