KCNH2 Variant V549L Detail

We estimate the penetrance of LQTS for KCNH2 V549L is 9%. We are unaware of any observations of this variant in individuals. V549L is not present in gnomAD. V549L 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 0 individuals with LQT2 and 10 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 V549L around 9% (0/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.875 0.79 1 0.867 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 10 0 -
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.

V549L 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
549 0 V549M,
548 4
550 5
546 5
547 5 A547T,
552 6 L552S,
543 6 S543fsX,
553 6 L553V,
662 7
551 7 F551L, F551L, F551L,
545 9
659 9
542 9
665 9 R665Q,
658 9
539 9
544 10 E544fsX, E544A,
554 10
555 10
666 10
674 10 H674fsX, H674Y,
661 10 A661V,
663 11
556 11
655 11
540 11 D540fsX,
412 11 W412X,
660 12 S660L,
657 12 G657V, G657S,
415 12
535 12 V535M,
656 12 F656L, F656L, F656L,
541 13 R541H, R541C,
671 13 A671Del, A671G,
670 13
678 13
536 13 A536X,
654 13
667 14 Y667X,
557 14
650 14 L650X,
664 14 Q664X,
675 14
673 14
538 14
681 14 R681W,
677 15 M677T,
667 15 Y667X,
419 15