KCNH2 Variant V503M Detail

We estimate the penetrance of LQTS for KCNH2 V503M is 22%. We are unaware of any observations of this variant in individuals. V503M is not present in gnomAD. V503M has not been functionally characterized. This residue is located in a Mild_Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 2 individuals with LQT2 and 8 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 V503M around 22% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.747 0.406 1 0.897 32
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 8 2 -
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.

V503M has 40 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
503 0
502 4 M502I, M502I, M502I,
504 4 A504V,
506 5 I506V,
505 6 A505V,
500 6 I500Del,
527 6
530 7
501 7 D501N, D501H, D501Y,
499 7
531 8 R531Del, R531W, R531Q,
498 9
528 9 R528X, R528W, R528P,
507 9 P507S, P507L,
526 10
524 10
508 10
529 10
463 10 F463L, F463L, F463L,
534 11 R534C,
467 11
533 11
464 11 I464X,
525 12 K525N, K525N,
460 12 D460fsX,
497 12 W497X, W497L,
496 13
532 13
493 13 Y493C, Y493Ins, Y493F, Y493H,
466 13 D466E, D466E,
421 13 T421M, T421fsX,
494 14 F494Del,
523 14
425 14
459 14
537 14 R537W,
418 15
461 15
522 15 G522E,
470 15 N470D,