Paralogue Annotation for SCN5A residue 216

Residue details

Gene: SCN5A
Reference Sequences: LRG: LRG_289, Ensembl variant: ENST00000333535 / ENSP00000328968
Amino Acid Position: 216
Reference Amino Acid: S - Serine
Protein Domain: TM Domain 1

Paralogue Variants mapped to SCN5A residue 216

ParalogueVariantAssociated DiseaseMapping QualityConsensusPubmed
SCN9AS211PErythermalgia, primaryHigh9 20123784
CACNA1AR192QHemiplegic migraine and episodic ataxia 2Medium9 8898206, 10024348, 15003170, 18581134, 19104150, 19242091, 20735819, 22144569, 9488686, 22956801, 22836594, 23985897, 24583041, 25481823, 25716839, 26208839
CACNA1AR192WEpisodic ataxia 2Medium9 25473036

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.

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See full Alignment of Paralogues

Known Variants in SCN5A

ProteinCDSDisease ClassificationDiseasedbSNP linksEffect Prediction
p.S216Lc.647C>T ConflictSIFT: deleterious
Polyphen: probably damaging
ReportsCardiomyopathyDCM Spectrum and prevalence of cardiac sodium channel variants among black, white, Asian, and Hispanic individuals: implications for arrhythmogenic susceptibility and Brugada/long QT syndrome genetic testing. Heart Rhythm. 2004 1(5):600-7. 15851227
Inherited ArrhythmiaLQTS Prevalence of long-QT syndrome gene variants in sudden infant death syndrome. Circulation. 2007 115(3):361-7. 17210839
CardiomyopathyDCM 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
Benign Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. Circulation. 2009 120(18):1752-60. 19841300
Benign 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
CardiomyopathyDCM A Brugada syndrome mutation (p.S216L) and its modulation by p.H558R polymorphism: standard and dynamic characterization. Cardiovasc Res. 2011 91(4):606-16. 21705349
CardiomyopathyDCM Cardiac sodium channel dysfunction in sudden infant death syndrome. Circulation. 2007 115(3):368-76. 17210841
Inherited ArrhythmiaLQTS High prevalence of genetic variants previously associated with LQT syndrome in new exome data. Eur J Hum Genet. 2012 20(8):905-8. doi: 10.1038/ejhg.2012.23. 22378279
Inherited ArrhythmiaAF High prevalence of long QT syndrome-associated SCN5A variants in patients with early-onset lone atrial fibrillation. Circ Cardiovasc Genet. 2012 5(4):450-9. doi: 10.1161/CIRCGENETICS.111.962597. 22685113
Inherited ArrhythmiaLQTS Vagal reflexes following an exercise stress test: a simple clinical tool for gene-specific risk stratification in the long QT syndrome. J Am Coll Cardiol. 2012 60(24):2515-24. doi: 10.1016/j.jacc.2012.08.1009. 23158531
Unknown New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants. Eur J Hum Genet. 2013 23299917
Inherited ArrhythmiaLQTS High prevalence of genetic variants previously associated with Brugada syndrome in new exome data. Clin Genet. 2013 23414114
Inherited ArrhythmiaLQTS Mutations in Genes Encoding Cardiac Ion Channels Previously Associated With Sudden Infant Death Syndrome (SIDS) Are Present With High Frequency in New Exome Data. Can J Cardiol. 2013 23465283
CardiomyopathyDCM Rare genetic variants previously associated with congenital forms of long QT syndrome have little or no effect on the QT interval. Eur Heart J. 2015 36(37):2523-9. doi: 10.1093/eurheartj/ehv297. 26159999
CardiomyopathyDCM Electrophysiological characterization of a large set of novel variants in the SCN5A-gene: identification of novel LQTS3 and BrS mutations. Pflugers Arch. 2016 468(8):1375-87. doi: 10.1007/s00424-016-1844-3. 27287068