D219V Summary

KCNH2 D219V was found in 1 paper (see below) with a total of 3 carriers: 1 had LQT2. D219V is present in 2 out of 99608 alleles in gnomAD (0.002008%). D219V has been functionally characterized in 1 paper. Given the functional data available, we estimate this variant has "GOF" in vitro character. (LOF and GOF denote loss-of-function and gain-of-function, respectively). 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 8 individuals unaffected with LQT2 and 2 individuals affected with LQT2.

D219V Reported Clinical Data

PMID Year Carriers Unaffected LQT2 Other disease
25914329 1 0 1
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts.

D219V Reported Functional Data: heterozygously collected

Steady state (S.S.) and peak tail current are relative % to wildtype (100% being no different from wildtype). V0.5 act/inact are the voltages at which half of the maximal current is reached during an activation and inactivation protocol, each is in units of mV and relative to wildtype. Recovery from inactivation (Rec. inact.) and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless).

PMID Year Cell type S.S. peak current (%WT) Peak tail current (%WT) V0.5 act V0.5 inact Rec. inact. (%WT) Deactivation (%WT)
25914329 2014 HEK293 206.9 -2.77 25.04

D219V Reported Functional Data: homozygously collected

PMID Year Cell type S.S. peak current (%WT) Peak tail current (%WT) V0.5 act V0.5 inact Rec. inact. (%WT) Deactivation (%WT)
25914329 2014 HEK293 207 7.26 24.00

D219V Predictions

PROVEAN scores less than -2 are considered deleterious. REVEL scores higher than 0.5 or 0.75 is 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. PAM scores reflect the chemistry difference between WT and variant amino acid (more negative being greater difference between the two). BLAST-PSSM reflects the evolutionary conservation of residue substitutions, more negative numbers indicate fewer observations of the specific substitution than is expected.

PAM Score REVEL Score PROVEAN Score Polyphen2 Score BLAST-PSSM
-8 0.604 -1.506 0.65 -3

D219V has 30 neighbors (found in individuals) within 15 ångströms

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. This results from the fact that the functional Kv11.1 channel 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.

ResidueNumber Distance(Å) Variants
204 14.7
205 14.2 P205L
206 13.7
207 13.2 S207X
208 12.6 E208X
209 12
210 11.4
211 10.7
212 10.1
213 9.3 D213G
214 8.5 E214X
215 7.6 V215G V215X
216 6.6 T216A
217 5.4
218 3.8
220 3.8
221 5.4
222 6.6 V222L
223 7.6
224 8.5
225 9.3
226 10.1
227 10.7
228 11.4 A228P A228T A228V A228X
229 12 E229X
230 12.6 E230D
231 13.2
232 13.7 R232C R232P
233 14.2 A233S
234 14.7 L234Del