KCNH2 Variant Y673D Detail

We estimate the penetrance of LQTS for KCNH2 Y673D is 15%. We are unaware of any observations of this variant in individuals. Y673D is not present in gnomAD. Y673D 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 Y673D around 15% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-9.689 1.0 -3 0.963 11
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.

Y673D has 49 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
673 0
674 4 H674fsX, H674Y,
677 6 M677T,
705 6 W705fsX, W705X,
670 6
669 7 G669R, G669X, G669C,
676 7 Q676X, Q676fsX,
671 7 A671G, A671Del,
701 7
672 7 R672C, R672H,
675 7
702 7
710 9
678 9
706 10 S706C, S706F,
543 10 S543fsX,
668 10 S668L,
540 10 D540fsX,
709 10
681 10 R681W,
704 10 A704T, A704V,
680 10
4 11
544 11 E544A, E544fsX,
679 11 R679Q, R679W,
3 11
698 11 E698X, E698K,
665 11 R665Q,
708 11
667 12 Y667X,
539 12
711 12 I711V,
703 12
700 13
697 13 L697X,
699 14 E699D, E699D,
546 14
682 14 E682X,
664 14 Q664X,
549 14 V549M,
707 14
541 14 R541H, R541C,
719 14
712 14 D712N,
716 14 V716G,
545 15
662 15
720 15
666 15