KCNH2 Variant P507L Detail

We estimate the penetrance of LQTS for KCNH2 P507L is 66%. This variant was found in a total of 1 carriers in 1 papers or gnomAD, 1 had LQTS. P507L is not present in gnomAD. P507L has not been functionally characterized. This residue is located in a Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 6 individuals with LQT2 and 4 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 P507L around 66% (7/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-9.333 0.998 -3 0.949 63
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
Japan Cohort 2020 1 0 1
LITERATURE, COHORT, AND GNOMAD: - 1 0 1 -
VARIANT FEATURES ALONE: - 10 4 6 -
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.

P507L has 37 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
507 0 P507L, P507S,
506 4 I506V,
508 5
505 6 A505V,
460 7 D460fsX,
504 8 A504V,
509 9 D509N,
528 9 R528W, R528X, R528P,
525 9 K525N, K525N,
503 9
464 9 I464X,
457 9 L457P,
524 10
510 10
527 10
502 10 M502I, M502I, M502I,
461 10
456 11 D456Y,
463 11 F463L, F463L, F463L,
531 11 R531Del, R531Q, R531W,
459 11
526 13
522 13 G522E,
458 13
521 13
467 13
501 13 D501Y, D501N, D501H,
530 14
453 14
462 14 M462Ins,
465 14
425 14
421 14 T421fsX, T421M,
523 14
529 15
454 15
500 15 I500Del,