| Paralogue | Variant | Associated Disease | Mapping Quality | Consensus | Pubmed |
|---|---|---|---|---|---|
| SCN4A | R222W | Hypokalaemic periodic paralysis | High | 9 | 19118277 |
| SCN11A | R225C | Episodic pain syndrome | High | 9 | 24207120 |
| SCN8A | R223G | Epileptic encephalopathy | High | 9 | 25239001, 25239001 |
| SCN2A | R220G | Epileptic encephalopathy | High | 9 | 25818041 |
| SCN1A | R219G | Dravet syndrome | High | 9 | 27236449 |
To assess whether the paralogue annotation here confidently predicts that variation at this residue is pathogenic, it is important to check the reports in the Pubmed links above to ascertain that the mutations in these paralogues have been proved likely to be disease-causing. It is also important to check that the direction of effect of the variant in the paralogue is compatible with your observed phenotype in SCN5A.
| SCN5A | NIKLG-----------------NLSALRTF>R<VLRALKTISVIPGLKTIVGALIQSVKKLAD | 252 |
| SCN1A | FVDLG-----------------NVSALRTF>R<VLRALKTISVIPGLKTIVGALIQSVKKLSD | 249 |
| SCN2A | FVDLG-----------------NVSALRTF>R<VLRALKTISVIPGLKTIVGALIQSVKKLSD | 250 |
| SCN3A | FVDLG-----------------NVSALRTF>R<VLRALKTISVIPGLKTIVGALIQSVKKLSD | 249 |
| SCN4A | FVDLG-----------------NISALRTF>R<VLRALKTITVIPGLKTIVGALIQSVKKLSD | 252 |
| SCN7A | YSPLD-----------------FIPTLQTA>R<TLRILKIIPLNQGLKSLVGVLIHCLKQLIG | 239 |
| SCN8A | FVNLG-----------------NVSALRTF>R<VLRALKTISVIPGLKTIVGALIQSVKKLSD | 253 |
| SCN9A | FVNLG-----------------NVSALRTF>R<VLRALKTISVIPGLKTIVGALIQSVKKLSD | 247 |
| SCN10A | AIDLR-----------------GISGLRTF>R<VLRALKTVSVIPGLKVIVGALIHSVKKLAD | 248 |
| SCN11A | IPGIT----------------IKLLPLRTF>R<VFRALKAISVVSRLKVIVGALLRSVKKLVN | 255 |
| CACNA1A | VGTEF-----------------DLRTLRAV>R<VLRPLKLVSGIPSLQVVLKSIMKAMIPLLQ | 228 |
| CACNA1B | AGTDF-----------------DLRTLRAV>R<VLRPLKLVSGIPSLQVVLKSIMKAMVPLLQ | 225 |
| CACNA1C | ILEQATKA-DGANALGGKGAGFDVKALRAF>R<VLRPLRLVSGVPSLQVVLNSIIKAMVPLLH | 270 |
| CACNA1D | ILEQLTKETEGGNHSSGKSGGFDVKALRAF>R<VLRPLRLVSGVPSLQVVLNSIIKAMVPLLH | 273 |
| CACNA1E | AGTHFN-------------THVDLRTLRAV>R<VLRPLKLVSGIPSLQIVLKSIMKAMVPLLQ | 223 |
| CACNA1F | LLEQGPGRPGDAPHTGGKPGGFDVKALRAF>R<VLRPLRLVSGVPSLHIVLNSIMKALVPLLH | 239 |
| CACNA1G | SLDLQ---------------NVSFSAVRTV>R<VLRPLRAINRVPSMRILVTLLLDTLPMLGN | 213 |
| CACNA1H | SLDGH---------------NVSLSAIRTV>R<VLRPLRAINRVPSMRILVTLLLDTLPMLGN | 232 |
| CACNA1I | SLDLQ---------------NINLSAIRTV>R<VLRPLKAINRVPSMRILVNLLLDTLPMLGN | 211 |
| CACNA1S | ILEQVNVIQSHTAPMSSKGAGLDVKALRAF>R<VLRPLRLVSGVPSLQVVLNSIFKAMLPLFH | 198 |
| cons | > < |
| Protein | CDS | Disease Classification | Disease | dbSNP links | Effect Prediction |
|---|---|---|---|---|---|
| p.R222Q | c.665G>A | Cardiomyopathy | LQTS,BrS,DCM | rs45546039 | SIFT: deleterious Polyphen: probably damaging |
| Reports | Cardiomyopathy | DCM | Coding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP from 313 patients with familial or idiopathic dilated cardiomyopathy. Clin Transl Sci. 2008 1(1):21-6. 19412328 | ||
| Inherited Arrhythmia | LQTS | Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. Heart Rhythm. 2009 6(9):1297-303. 19716085 | |||
| Inherited Arrhythmia | BrS | An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing. Heart Rhythm. 2010 7(1):33-46. 20129283 | |||
| Other Cardiac Phenotype | Multifocal ectopic Purkinje-related premature contractions: a new SCN5A-related cardiac channelopathy. J Am Coll Cardiol. 2012 60(2):144-56. doi: 10.1016/j.jacc.2012.02.052. 22766342 | ||||
| Cardiomyopathy | DCM | Escape capture bigeminy: phenotypic marker of cardiac sodium channel voltage sensor mutation R222Q. Heart Rhythm. 2012 9(10):1681-1688.e1. doi: 10.1016/j.hrthm.2012.06.0 22710484 | |||
| Cardiomyopathy | DCM | R222Q SCN5A mutation is associated with reversible ventricular ectopy and dilated cardiomyopathy. J Am Coll Cardiol. 2012 60(16):1566-73. doi: 10.1016/j.jacc.2012.05.050. 22999724 | |||
| Inherited Arrhythmia | BrS | Paralogue annotation identifies novel pathogenic variants in patients with Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia. J Med Genet. 2014 51(1):35-44. doi: 10.1136/jmedgenet-2013-101917. 24136861 | |||
| Unknown | SCN5A rare variants in familial dilated cardiomyopathy decrease peak sodium current depending on the common polymorphism H558R and common splice variant Q1077del. Clin Transl Sci. 2010 3(6):287-94. doi: 10.1111/j.1752-8062.2010.00249.x 21167004 | ||||
| Cardiomyopathy | DCM | Novel SCN5A mutation in amiodarone-responsive multifocal ventricular ectopy-associated cardiomyopathy. Heart Rhythm. 2014 11(8):1446-53. doi: 10.1016/j.hrthm.2014.04.042. 24815523 | |||
| Cardiomyopathy | DCM | Gating pore currents are defects in common with two Nav1.5 mutations in patients with mixed arrhythmias and dilated cardiomyopathy. J Gen Physiol. 2015 145(2):93-106. doi: 10.1085/jgp.201411304. 25624448 | |||
| p.Arg222Gly | c.664C>G | Unknown | SIFT: Polyphen: | ||