Paralogue Annotation for SCN5A residue 615

Residue details

Gene: SCN5A
Reference Sequences: LRG: LRG_289, Ensembl variant: ENST00000333535 / ENSP00000328968
Amino Acid Position: 615
Reference Amino Acid: G - Glycine
Protein Domain: Interdomain Linker I-II

Paralogue Variants mapped to SCN5A residue 615

Paralogue	Variant	Associated Disease	Mapping Quality	Consensus	Pubmed
SCN9A	N641Y	Febrile seizures	Low	1	19763161

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	-----DCNGVVSLLG-AGD----PEAT-SP>G<SHLLRP-------------VMLEHPP--DT	630
SCN1A	MHSTVDCNGVVSLVG-G-P----SVPT-SP>V<GQLLPE-------------VIIDKPATDDN	681
SCN2A	MHSAVDCNGVVSLVG-G-P----STLT-SA>-<GQLLPE------------------------	672
SCN3A	MHSTVDCNGVVSLVG-G-P----SALT-SP>T<GQLPPE------------------------	673
SCN4A	-----DCNGSLDTSQ-G------------->-<------------------------------	515
SCN7A	------------------------------>-<------------------------------
SCN8A	RNSTVDCNGVVSLIG-G-P----GSHI--->G<GRLLPE------------------------	666
SCN9A	MHSAVDCNGVVSLVD-G-R----SALM-LP>N<GQLLPE-------------G----------	648
SCN10A	------------SRH-G-E----DEHQPPP>T<-SELAP----------------------GA	581
SCN11A	-----DCQKKPQLLE-Q------------->-<----T-------------------------	498
CACNA1A	------------------------------>-<------------------------------
CACNA1B	------------------------------>-<------------------------------
CACNA1C	------------------------------>-<------------------------------
CACNA1D	------------------------------>-<------------------------------
CACNA1E	------------------------------>-<------------------------------
CACNA1F	------------------------------>-<------------------------------
CACNA1G	LVEVAASSGPPTLTSL-NI----PPGPY-S>S<MHKLLETQSTGACQS-----SC--KISSPC	654
CACNA1H	PGPKGKWAGGPPGTGGHGPLSLNSPDPY-E>K<IPHVVGEHGLGQAPGHLSGLSV--PCPLPS	687
CACNA1I	-----TLAS--------------------->-<------------------------------	548
CACNA1S	------------------------------>-<------------------------------
cons	> <

See full Alignment of Paralogues

Known Variants in SCN5A

Protein	CDS	Disease Classification	Disease	dbSNP links	Effect Prediction
p.G615E	c.1844G>A	Inherited Arrhythmia	LQTS,BrS	rs12720452	SIFT: tolerated Polyphen: benign
Reports		Other Cardiac Phenotype		Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes. Circulation. 2002 105(16):1943-8. 11997281
		Inherited Arrhythmia	LQTS	Genetic variations of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 in drug-induced long QT syndrome patients. J Mol Med (Berl). 2004 82(3):182-8. 14760488
		Inherited Arrhythmia	LQTS	Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. Heart Rhythm. 2005 2(5):507-17. 15840476
		Other Cardiac Phenotype		Cardiac sodium channel gene variants and sudden cardiac death in women. Circulation. 2008 117(1):16-23. 18071069
		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	LQTS	Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. Circulation. 2009 120(18):1752-60. 19841300
		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		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
		Other Cardiac Phenotype		High prevalence of genetic variants previously associated with Brugada syndrome in new exome data. Clin Genet. 2013 23414114
		Inherited Arrhythmia	LQTS	Results of genetic testing in 855 consecutive unrelated patients referred for long QT syndrome in a clinical laboratory. Genet Test Mol Biomarkers. 2013 17(7):553-61. doi: 10.1089/gtmb.2012.0118. 23631430
		Inherited Arrhythmia	LQTS	Actionable, pathogenic incidental findings in 1,000 participants' exomes. Am J Hum Genet. 2013 93(4):631-40. doi: 10.1016/j.ajhg.2013.08.006. 24055113
		Other Disease Phenotype		Loss-of-function of the voltage-gated sodium channel NaV1.5 (channelopathies) in patients with irritable bowel syndrome. Gastroenterology. 2014 146(7):1659-68. doi: 10.1053/j.gastro.2014.02.054. 24613995
		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
		Inherited Arrhythmia	BrS	Testing the burden of rare variation in arrhythmia-susceptibility genes provides new insights into molecular diagnosis for Brugada syndrome. Hum Mol Genet. 2015 24(10):2757-63. doi: 10.1093/hmg/ddv036. 25650408
		Other Cardiac Phenotype		Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer. Am J Hum Genet. 2016 98(5):801-17. doi: 10.1016/j.ajhg.2016.02.024. 27153395