ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.1099C>T (p.Arg367Cys) (rs199473097)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058389 SCV000089909 not provided Congenital long QT syndrome no assertion provided literature only This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Fulgent Genetics,Fulgent Genetics RCV000763108 SCV000893650 pathogenic Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1, autosomal recessive; Progressive familial heart block type 1A; Paroxysmal familial ventricular fibrillation 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000182957 SCV000235354 pathogenic not provided 2017-06-09 criteria provided, single submitter clinical testing The R367C likely pathogenic variant in the SCN5A gene has been reported in several individuals with definitive or suspected Brugada syndrome or LQTS (Smits et al., 2002; Kapplinger et al., 2010; Amin et al., 2011; Walsh et al, 2014). One reported individual with Brugada syndrome and two individuals referred for LQTS genetic testing had sudden cardiac death (Meregalli et al., 2009; Kapplinger, 2009). This variant was not observed in over 2,600 published control alleles from individuals of various ethnic backgrounds (Kapplinger, 2009; Kapplinger, 2010; Walsh et al, 2014), and was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R367C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution also occurs at a position that is conserved across species. Furthermore, the R367C variant resulted in 100% reduction of peak sodium current in patch-clamp studies (Meregalli et al. 2009), consistent with haploinsufficiency, which is the known mechanism of disease in SCN5A-associated Brugada syndrome. Moreover, a missense variant in the same residue (R367H) has been reported in the Human Gene Mutation Database in association with arrhythmia (Stenson et al., 2014), supporting the functional importance of this residue of the protein. Therefore, we interpret this variant as pathogenic.
Invitae RCV000466350 SCV000545008 likely pathogenic Brugada syndrome 2017-12-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 367 of the SCN5A protein (p.Arg367Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs199473097, ExAC 0.009%). This variant has been reported in the literature in several individuals affected with Brugada syndrome (PMID: 21273195, 20129283), primary electrical disease (PMID: 28341588), and unexplained cardiac arrest (PMID: 28600387). ClinVar contains an entry for this variant (Variation ID: 67633). Experimental studies have suggested that this missense change causes a complete loss of sodium current; however, additional data are not available in the publication (PMID: 19251209). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. A different missense substitution at this codon (p.Arg367His) is reported to be deleterious (PMID: 11823453, 20129283). This indicates that the arginine residue is important for SCN5A protein function. For these reasons, this variant has been classified as Likely Pathogenic.

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