KCNQ1 Variant G568V Detail

We estimate the penetrance of LQTS for KCNQ1 G568V is 82%. We are unaware of any observations of this variant in individuals. G568V is not present in gnomAD. G568V has not been functionally characterized. This residue is located in a Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 8 individuals with LQT1 and 2 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 G568V around 82% (8/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.89 1.0 -3 0.942 92
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 LQT1 Other Disease
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.

G568V 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. This results from the fact that the functional KV7.1 channel 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
568 0 G568R, G568R, G568E,
567 4 I567T, I567S,
569 4 K569E,
566 5 S566F, S566Y, S566P,
570 5 P570L,
565 7
571 7 S571L, S571P,
564 8 D564H, D564N,
572 8
563 8
573 8 F573L, F573L, F573L,
562 9 R562M, R562S, R562S,
574 9 I574V,
561 10
575 10
560 11
576 11 V576I,
559 11 L559P,
577 11
558 12
578 12 E578K, E578V,
557 13 K557E,
579 13
556 13
580 13 S580G, S580N,
555 14 R555H, R555C, R555S, R555L,
581 14
554 14
582 14
553 15
583 15 R583H, R583C, R583G,