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

Paralogue	Variant	Associated Disease	Mapping Quality	Consensus	Pubmed
SCN9A	S211P	Erythermalgia, primary	High	9	20123784
CACNA1A	R192Q	Hemiplegic migraine and episodic ataxia 2	Medium	9	8898206, 10024348, 15003170, 18581134, 19104150, 19242091, 20735819, 22144569, 9488686, 22956801, 22836594, 23985897, 24583041, 25481823, 25716839, 26208839
CACNA1A	R192W	Episodic ataxia 2	Medium	9	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.

SCN5A	MAYVSENIKLG-----------------NL>S<ALRTFRVLRALKTISVIPGLKTIVGALIQS	246
SCN1A	FAYVTEFVDLG-----------------NV>S<ALRTFRVLRALKTISVIPGLKTIVGALIQS	243
SCN2A	FAYVTEFVDLG-----------------NV>S<ALRTFRVLRALKTISVIPGLKTIVGALIQS	244
SCN3A	MAYVTEFVDLG-----------------NV>S<ALRTFRVLRALKTISVIPGLKTIVGALIQS	243
SCN4A	MAYLTEFVDLG-----------------NI>S<ALRTFRVLRALKTITVIPGLKTIVGALIQS	246
SCN7A	FEVIIRYSPLD-----------------FI>P<TLQTARTLRILKIIPLNQGLKSLVGVLIHC	233
SCN8A	MAYITEFVNLG-----------------NV>S<ALRTFRVLRALKTISVIPGLKTIVGALIQS	247
SCN9A	FAYLTEFVNLG-----------------NV>S<ALRTFRVLRALKTISVIPGLKTIVGALIQS	241
SCN10A	LAYVGTAIDLR-----------------GI>S<GLRTFRVLRALKTVSVIPGLKVIVGALIHS	242
SCN11A	IAIVSYIPGIT----------------IKL>L<PLRTFRVFRALKAISVVSRLKVIVGALLRS	249
CACNA1A	TGILATVGTEF-----------------DL>R<TLRAVRVLRPLKLVSGIPSLQVVLKSIMKA	222
CACNA1B	TGILATAGTDF-----------------DL>R<TLRAVRVLRPLKLVSGIPSLQVVLKSIMKA	219
CACNA1C	VGLFSAILEQATKA-DGANALGGKGAGFDV>K<ALRAFRVLRPLRLVSGVPSLQVVLNSIIKA	264
CACNA1D	VGLFSVILEQLTKETEGGNHSSGKSGGFDV>K<ALRAFRVLRPLRLVSGVPSLQVVLNSIIKA	267
CACNA1E	SGILATAGTHFN-------------THVDL>R<TLRAVRVLRPLKLVSGIPSLQIVLKSIMKA	217
CACNA1F	VGLFSVLLEQGPGRPGDAPHTGGKPGGFDV>K<ALRAFRVLRPLRLVSGVPSLHIVLNSIMKA	233
CACNA1G	AGMLEYSLDLQ---------------NVSF>S<AVRTVRVLRPLRAINRVPSMRILVTLLLDT	207
CACNA1H	AGMMEYSLDGH---------------NVSL>S<AIRTVRVLRPLRAINRVPSMRILVTLLLDT	226
CACNA1I	AGMVEYSLDLQ---------------NINL>S<AIRTVRVLRPLKAINRVPSMRILVNLLLDT	205
CACNA1S	LGVFTVILEQVNVIQSHTAPMSSKGAGLDV>K<ALRAFRVLRPLRLVSGVPSLQVVLNSIFKA	192
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See full Alignment of Paralogues

Known Variants in SCN5A

Protein	CDS	Disease Classification	Disease	dbSNP links	Effect Prediction
p.S216L	c.647C>T	Conflict		rs41276525	SIFT: deleterious Polyphen: probably damaging
Reports		Cardiomyopathy	DCM	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 Arrhythmia	LQTS	Prevalence of long-QT syndrome gene variants in sudden infant death syndrome. Circulation. 2007 115(3):361-7. 17210839
		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
		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
		Cardiomyopathy	DCM	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
		Cardiomyopathy	DCM	Cardiac sodium channel dysfunction in sudden infant death syndrome. Circulation. 2007 115(3):368-76. 17210841
		Inherited Arrhythmia	LQTS	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 Arrhythmia	AF	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 Arrhythmia	LQTS	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 Arrhythmia	LQTS	High prevalence of genetic variants previously associated with Brugada syndrome in new exome data. Clin Genet. 2013 23414114
		Inherited Arrhythmia	LQTS	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
		Cardiomyopathy	DCM	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
		Cardiomyopathy	DCM	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