A226V Summary

SCN5A A226V was found in 6 papers (see below) with a total of 36 carriers: 4 had BrS1, 0 had LQT3, and 1 had other disease. A226V is present in 27 out of 272372 alleles in gnomAD (minor allele frequency of 0.009913%). A226V has been functionally characterized in 2 papers. Other variants at the same resdue are A226D .A226G .A226P .A226S .A226T .A226V . Given the functional data available, we estimate this variant has "Partial_LOF" 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 BrS1 and in a Non_Hotspot region for Long QT syndrome.

A226V Reported Clinical Data

PMID Year Unaffected BrS LQT3 Other Other disease
2582947320152100
3005013720180000
1190104620020100
1496785320043100
2877900320170001DCM
2012928320100200
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts.

A226V Reported Functional Data

Peak current and late current are relative % to 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.

PMID Year Cell type Peak current V0.5 act V0.5 inact Rec from inact Late current
25829473 2015 tsA201 24.3 NA
30050137 2018 tsA201 46.7 3.21 -0.16 NA

A226V 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.

SIFT Sift Score PROVEAN Score Polyphen2 Polyphen2 Score eaRate blastPssm pamScore REVEL
Damaging 0.03 -3.75 probablydamaging 0.998 0.3081 1.08 -2 0.891

A226V has 62 neighbors within 15 ångströms that have been found in individuals.

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.

ResidueNumber Distance(Å) Variants
134 14.8
137 11.6 I137V
138 8.7
139 11.9
140 10.7
141 6.2 I141N I141V
142 8
143 11.1
144 8.4
145 6.9
146 11.6 V146A V146M
147 13.1
148 9.6
149 13.4
164 12.9
168 11.7
171 14.4
192 14.2
193 10.6
194 13.8
195 14
196 9.5
197 10.3
198 14.6
199 13.2
200 10.2
201 12.9
203 14.2
204 14.5
219 14.9 R219C
220 13.1 T220I
221 11.7
222 10.3 R222Q
223 6 V223L
224 6.2
225 5.6 R225Q R225W
227 4.2 L227P
228 6.2
229 5
230 7.6 I230T I230V
231 9.8
232 10.8 V232I
233 11.9
236 13.9
240 13.6 V240M
844 11.7
845 10.5
846 13
847 10.4
848 6.6 I848F
849 9.4
850 11.2 V850M
851 7.4 F851L F851L F851L
852 6.4
853 11.3
854 11.9
855 10.1
856 11.6
857 14.8 G857D
858 14.8 M858L M858L
884 14.1
925 15