KCNH2 Variant Y475N Detail

We estimate the penetrance of LQTS for KCNH2 Y475N is 77%. We are unaware of any observations of this variant in individuals. Y475N is not present in gnomAD. Y475N 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 7 individuals with LQT2 and 3 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 Y475N around 77% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-8.315 0.999 -2 0.943 81
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 3 7 -
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.

Y475N has 47 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
475 0 Y475Del, Y475C,
483 5 V483I,
476 5 V476I,
474 5 T474I,
477 6
489 6 I489F, I489I,
492 6 H492Y,
482 7 V482A,
484 8
473 8 T473P,
480 8 E480V,
402 8 H402R,
481 8
488 9 R488H, R488C,
478 9 A478D,
490 10 A490T, A490P,
493 10 Y493C, Y493H, Y493Ins, Y493F,
491 10 V491I,
470 10 N470D,
6 10 G6R,
4 11
487 11 G487R, G487S,
485 11 H485X,
401 11
471 11 F471X,
479 11
486 11
400 12 I400N,
537 12 R537W,
403 12
472 12 R472X, R472C,
496 12
5 12
497 13 W497X, W497L,
494 13 F494Del,
3 13
407 13
469 13
538 13
399 13
8 13
495 14 K495X,
9 14 A9T, A9V,
404 14
498 14
7 14
541 15 R541C, R541H,