KCNH2 Variant D580N Detail

We estimate the penetrance of LQTS for KCNH2 D580N is 14%. We are unaware of any observations of this variant in individuals. D580N is not present in gnomAD. D580N 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 D580N around 14% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.003 0.006 3 0.522 25
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.

D580N has 31 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
580 0 D580Y,
579 4 M579V, M579I, M579T, M579I, M579I,
581 4
578 5
582 5 R582H, R582C, R582L, R582P,
577 7
583 7 I583V,
576 8
584 8 G584S, G584C, G584R,
575 8 E575K,
585 8 W585C, W585C,
574 9 M574V, M574L, M574L,
586 9 L586M,
573 10
587 10
572 11 G572D, G572R, G572C, G572S,
588 11 N588K, N588D, N588K,
571 11 I571V, I571L,
589 11 L589P,
570 12
590 12 G590D, G590V,
569 13 Y569H, Y569C, Y569X,
591 13 D591N, D591H,
568 13 W568C, W568C,
592 13 Q592X,
567 14 I567M, I567T,
593 14 I593R, I593K, I593V, I593T, I593X,
566 14 C566G, C566F, C566S, C566S, C566R,
594 14
565 15
595 15 K595E, K595N, K595N,