KCNH2 Variant T670S Detail

We estimate the penetrance of LQTS for KCNH2 T670S is 13%. We are unaware of any observations of this variant in individuals. T670S is not present in gnomAD. T670S 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 T670S around 13% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.701 0.946 1 0.849 17
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.

T670S 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
670 0
669 4 G669C, G669X, G669R,
671 4 A671Del, A671G,
668 6 S668L,
673 6
667 6 Y667X,
674 6 H674Y, H674fsX,
672 6 R672H, R672C,
705 8 W705fsX, W705X,
666 9
664 9 Q664X,
675 9
710 10
709 10
543 10 S543fsX,
663 11
539 11
540 11 D540fsX,
676 11 Q676X, Q676fsX,
677 11 M677T,
665 11 R665Q,
658 12
706 12 S706F, S706C,
665 12 R665Q,
702 12
701 13
678 13
549 13 V549M,
711 13 I711V,
662 13
708 13
682 13 E682X,
661 13 A661V,
661 13 A661V,
662 14
544 14 E544A, E544fsX,
536 14 A536X,
4 14
704 14 A704V, A704T,
678 14
654 14
546 14
3 14
657 15 G657V, G657S,
660 15 S660L,
679 15 R679W, R679Q,
553 15 L553V,