KCNH2 Variant V465A Detail

We estimate the penetrance of LQTS for KCNH2 V465A is 13%. We are unaware of any observations of this variant in individuals. V465A is not present in gnomAD. We have tested the trafficking efficiency of this variant, 88% of WT with a standard error of 14%; in our analysis we used SE < 20% as 'high quality'. Approximately below 50% of WT is considered PS3 moderate and below 30% is PS3 strong. V465A 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 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 V465A around 13% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.44 0.41 -1 0.832 56
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.

V465A has 38 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
465 0
464 5 I464X,
466 5 D466E, D466E,
468 5 L468F, L468X, L468R,
462 5 M462Ins,
469 6
467 6
461 6
463 7 F463L, F463L, F463L,
410 8 W410X,
470 9 N470D,
460 10 D460fsX,
459 10
505 10 A505V,
471 10 F471X,
414 10 I414fsX,
458 11
534 11 R534C,
407 12
413 12 L413P,
472 12 R472X, R472C,
417 12
501 12 D501H, D501N, D501Y,
406 12
473 12 T473P,
504 12 A504V,
531 12 R531Del, R531Q, R531W,
502 13 M502I, M502I, M502I,
411 13
457 13 L457P,
400 13 I400N,
493 13 Y493C, Y493F, Y493H, Y493Ins,
498 13
507 14 P507S, P507L,
506 14 I506V,
418 14
409 15 V409L, V409M, V409L,
456 15 D456Y,