KCNH2 Variant A548D Detail

We estimate the penetrance of LQTS for KCNH2 A548D is 12%. We are unaware of any observations of this variant in individuals. A548D is not present in gnomAD. A548D has not been functionally characterized. This residue is located in a Non_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 A548D around 12% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.751 0.998 -2 0.941 8
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.

A548D has 45 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
548 0
547 4 A547T,
549 4 V549M,
546 5
551 6 F551L, F551L, F551L,
550 6
545 6
552 6 L552S,
543 7 S543fsX,
542 8
412 9 W412X,
544 9 E544A, E544fsX,
553 9 L553V,
662 10
555 10
666 11
554 11
415 11
539 11
665 11 R665Q,
659 11
540 11 D540fsX,
541 12 R541H, R541C,
556 12
663 12
674 12 H674Y, H674fsX,
535 13 V535M,
658 13
416 13
411 13
661 13 A661V,
655 14
408 14
419 14
678 14
667 14 Y667X,
409 14 V409L, V409M, V409L,
681 14 R681W,
538 14
536 15 A536X,
660 15 S660L,
3 15
413 15 L413P,
650 15 L650X,
414 15 I414fsX,