KCNH2 Variant D501G Detail

We estimate the penetrance of LQTS for KCNH2 D501G is 74%. We are unaware of any observations of this variant in individuals. D501G is not present in gnomAD. D501G 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 7 individuals with LQT2 and 3 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 D501G around 74% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.487 0.997 -2 0.973 78
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 3 7 -
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.

D501G has 51 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
501 0 D501H, D501Y, D501N,
500 5 I500Del,
502 5 M502I, M502I, M502I,
534 5 R534C,
498 6
504 6 A504V,
503 7
499 7
467 7
530 7
497 7 W497X, W497L,
533 7
531 8 R531Q, R531W, R531Del,
505 8 A505V,
493 8 Y493Ins, Y493H, Y493F, Y493C,
463 8 F463L, F463L, F463L,
466 8 D466E, D466E,
537 8 R537W,
496 9
470 9 N470D,
464 10 I464X,
532 10
506 10 I506V,
527 10
538 11
494 11 F494Del,
535 11 V535M,
471 11 F471X,
536 12 A536X,
529 12
414 12 I414fsX,
465 12
468 12 L468R, L468X, L468F,
528 12 R528P, R528X, R528W,
418 12
469 12
460 13 D460fsX,
462 13 M462Ins,
495 13 K495X,
492 13 H492Y,
421 13 T421fsX, T421M,
417 13
507 13 P507S, P507L,
459 14
411 14
490 14 A490T, A490P,
461 14
410 14 W410X,
473 14 T473P,
526 14
415 15