ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.5476C>T (p.Arg1826Cys) (rs199473635)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183122 SCV000235533 likely pathogenic not provided 2012-06-11 criteria provided, single submitter clinical testing p.Arg1826Cys (CGT>TGT): c.5476 C>T in exon 28 of the SCN5A gene (NM_198056.2) The Arg1826Cys variant in the SCN5A gene has been reported previously in one individual with a history of atrial fibrillation, coronary artery disease and hypertension, and this variant was absent from 720 control alleles (Darbar D et al., 2008). The NHLBI ESP Exome Variant Server reports Arg1826Cys was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. A variant at the same codon, Arg1826His, has been reported in one case of SIDS (Ackerman M et al., 2001). However, neither variant at this position has been reported in patients confirmed to have LQTS or Brugada syndrome, to our knowledge. Arg1826Cys results in a non-conservative amino acid substitution of a positively charged Arginine with a neutral, polar Cysteine at a residue that is conserved across species. Mutations in nearby codons (Pro1824Ala, Gln1832Glu) have been reported in association with LQTS and Brugada syndrome, supporting the functional importance of this region of the protein. In summary, while Arg1826Cys in the SCN5A gene is a good candidate for a disease-causing mutation, the clinical significance of this variant is currently unknown. The variant is found in POSTMORTEM panel(s).
Invitae RCV000540654 SCV000637181 uncertain significance Brugada syndrome 2019-04-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1826 of the SCN5A protein (p.Arg1826Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs199473635, ExAC 0.004%). This variant was reported in an individual affected with atrial fibrillation (PMID: 18378609) and also in a healthy control individual (PMID: 25904541) . ClinVar contains an entry for this variant (Variation ID: 67994). This variant identified in the SCN5A gene is located in the cytoplasmic C-terminal region of the resulting protein (PMID: 25348405). For more information about the location of this variant, please visit www.invitae.com/SCN5A-topology. 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. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Color Health, Inc RCV001177883 SCV001342180 uncertain significance Arrhythmia 2019-06-13 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058785 SCV000090305 not provided Atrial fibrillation no assertion provided literature only This variant has been reported as associated with Atrial fibrillation in the following publications (PMID:18378609). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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