| Paralogue | Variant | Associated Disease | Mapping Quality | Consensus | Pubmed |
|---|---|---|---|---|---|
| SCN2A | R223Q | Neonatal-infantile seizures | High | 9 | 15048894 |
| SCN4A | R225W | Myotonia, non-dystrophic | High | 9 | 20076800, 26700687 |
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 | LG-----------------NLSALRTFRVL>R<ALKTISVIPGLKTIVGALIQSVKKLADVMV | 255 |
| SCN1A | LG-----------------NVSALRTFRVL>R<ALKTISVIPGLKTIVGALIQSVKKLSDVMI | 252 |
| SCN2A | LG-----------------NVSALRTFRVL>R<ALKTISVIPGLKTIVGALIQSVKKLSDVMI | 253 |
| SCN3A | LG-----------------NVSALRTFRVL>R<ALKTISVIPGLKTIVGALIQSVKKLSDVMI | 252 |
| SCN4A | LG-----------------NISALRTFRVL>R<ALKTITVIPGLKTIVGALIQSVKKLSDVMI | 255 |
| SCN7A | LD-----------------FIPTLQTARTL>R<ILKIIPLNQGLKSLVGVLIHCLKQLIGVII | 242 |
| SCN8A | LG-----------------NVSALRTFRVL>R<ALKTISVIPGLKTIVGALIQSVKKLSDVMI | 256 |
| SCN9A | LG-----------------NVSALRTFRVL>R<ALKTISVIPGLKTIVGALIQSVKKLSDVMI | 250 |
| SCN10A | LR-----------------GISGLRTFRVL>R<ALKTVSVIPGLKVIVGALIHSVKKLADVTI | 251 |
| SCN11A | IT----------------IKLLPLRTFRVF>R<ALKAISVVSRLKVIVGALLRSVKKLVNVII | 258 |
| CACNA1A | EF-----------------DLRTLRAVRVL>R<PLKLVSGIPSLQVVLKSIMKAMIPLLQIGL | 231 |
| CACNA1B | DF-----------------DLRTLRAVRVL>R<PLKLVSGIPSLQVVLKSIMKAMVPLLQIGL | 228 |
| CACNA1C | QATKA-DGANALGGKGAGFDVKALRAFRVL>R<PLRLVSGVPSLQVVLNSIIKAMVPLLHIAL | 273 |
| CACNA1D | QLTKETEGGNHSSGKSGGFDVKALRAFRVL>R<PLRLVSGVPSLQVVLNSIIKAMVPLLHIAL | 276 |
| CACNA1E | HFN-------------THVDLRTLRAVRVL>R<PLKLVSGIPSLQIVLKSIMKAMVPLLQIGL | 226 |
| CACNA1F | QGPGRPGDAPHTGGKPGGFDVKALRAFRVL>R<PLRLVSGVPSLHIVLNSIMKALVPLLHIAL | 242 |
| CACNA1G | LQ---------------NVSFSAVRTVRVL>R<PLRAINRVPSMRILVTLLLDTLPMLGNVLL | 216 |
| CACNA1H | GH---------------NVSLSAIRTVRVL>R<PLRAINRVPSMRILVTLLLDTLPMLGNVLL | 235 |
| CACNA1I | LQ---------------NINLSAIRTVRVL>R<PLKAINRVPSMRILVNLLLDTLPMLGNVLL | 214 |
| CACNA1S | QVNVIQSHTAPMSSKGAGLDVKALRAFRVL>R<PLRLVSGVPSLQVVLNSIFKAMLPLFHIAL | 201 |
| cons | > < |
| Protein | CDS | Disease Classification | Disease | dbSNP links | Effect Prediction |
|---|---|---|---|---|---|
| p.R225Q | c.674G>A | Inherited Arrhythmia | LQTS | rs199473071 | SIFT: deleterious Polyphen: probably damaging |
| Reports | Inherited Arrhythmia | LQTS | Spectrum of pathogenic mutations and associated polymorphisms in a cohort of 44 unrelated patients with long QT syndrome. Clin Genet. 2006 70(3):214-27. 16922724 | ||
| Inherited Arrhythmia | LQTS | 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 | |||
| p.R225W | c.673C>T | Inherited Arrhythmia | LQTS,BrS | rs199473072 | SIFT: deleterious Polyphen: probably damaging |
| Reports | Other Cardiac Phenotype | Compound heterozygosity for mutations (W156X and R225W) in SCN5A associated with severe cardiac conduction disturbances and degenerative changes in the conduction system. Circ Res. 2003 92(2):159-68. 12574143 | |||
| Inherited Arrhythmia | BrS | Type of SCN5A mutation determines clinical severity and degree of conduction slowing in loss-of-function sodium channelopathies. Heart Rhythm. 2009 6(3):341-8. 19251209 | |||
| 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 | |||
| Inherited Arrhythmia | BrS | The genetic basis of Brugada syndrome: a mutation update. Hum Mutat. 2009 30(9):1256-66. 19606473 | |||
| 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 | |||
| Other Cardiac Phenotype | Brugada syndrome disease phenotype explained in apparently benign sodium channel mutations. Circ Cardiovasc Genet. 2014 7(2):123-31. doi: 10.1161/CIRCGENETICS.113.000292. 24573164 | ||||
| Unknown | Actionable exomic incidental findings in 6503 participants: challenges of variant classification. Genome Res. 2015 25(3):305-15. doi: 10.1101/gr.183483.114. 25637381 | ||||
| Other Cardiac Phenotype | 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.R225P | c.674G>C | Cardiomyopathy | SIFT: Polyphen: | ||
| Reports | Cardiomyopathy | 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 | Mutations in the Voltage Sensors of Domains I and II of Nav1.5 that are Associated with Arrhythmias and Dilated Cardiomyopathy Generate Gating Pore Currents. Front Pharmacol. 2015 6:301. doi: 10.3389/fphar.2015.00301. eCollection 26733869 | ||||
| Cardiomyopathy | Intracellular calcium attenuates late current conducted by mutant human cardiac sodium channels. Circ Arrhythm Electrophysiol. 2015 8(4):933-41. doi: 10.1161/CIRCEP.115.002760. 26022185 | ||||