KCNH2 Variant R472P Detail

We estimate the penetrance of LQTS for KCNH2 R472P is 19%. We are unaware of any observations of this variant in individuals. R472P is not present in gnomAD. R472P 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 R472P around 19% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.487 1.0 -2 0.986 21
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 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.

R472P has 34 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
472 0 R472X, R472C,
398 6 W398X, W398L,
471 6 F471X,
486 6
473 6 T473P,
399 7
400 7 I400N,
469 7
468 8 L468R, L468X, L468F,
485 8 H485X,
489 8 I489I, I489F,
470 9 N470D,
474 9 T474I,
484 10
490 10 A490P, A490T,
487 10 G487R, G487S,
401 11
467 11
493 11 Y493F, Y493C, Y493H, Y493Ins,
465 12
466 12 D466E, D466E,
483 12 V483I,
475 12 Y475C, Y475Del,
488 12 R488H, R488C,
407 13
406 13
402 13 H402R,
491 14 V491I,
494 14 F494Del,
492 14 H492Y,
404 14
464 14 I464X,
498 15
410 15 W410X,