ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.2066G>A (p.Arg689His) (rs199473145)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000617789 SCV000738162 uncertain significance Cardiovascular phenotype 2017-09-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Conflicting evidence
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000148852 SCV000055301 uncertain significance Long QT syndrome 2018-04-05 criteria provided, single submitter research
CSER_CC_NCGL; University of Washington Medical Center RCV000148852 SCV000190596 uncertain significance Long QT syndrome 2014-06-01 no assertion criteria provided research
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058477 SCV000089997 not provided not provided no assertion provided literature only This variant has been reported in the following publications (PMID:15851227;PMID:16414944;PMID:19841300;PMID:21321465;PMID:20129283;PMID:22378279).
GeneDx RCV000058477 SCV000235399 uncertain significance not provided 2018-03-29 criteria provided, single submitter clinical testing The R689H variant of uncertain significance in the SCN5A gene has been reported in several individuals with arrhythmia, and was absent in approximately 1000 control alleles (Napolitano et al., 2005; Nakajima et al., 2011; Hong et al., 2012). Nevertheless, Ackerman et al. (2004), Kapplinger et al. (2010), and the NHLBI Exome Sequencing Project report that R689H is present at a low frequency in control alleles. The R689H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In addition, this substitution occurs at a position that is not conserved across species. However, functional studies showed that the R689H variant resulted in loss of channel function (Hong et al., 2012). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Illumina Clinical Services Laboratory,Illumina RCV000779408 SCV000916020 uncertain significance SCN5A-Related Arrhythmias 2019-01-07 criteria provided, single submitter clinical testing Several studies have reported patients with arrhythmias who are heterozygous for the SCN5A c.2066G>A (p.Arg689His) missense variant (Maekawa et al., 2005; Napolitano et al., 2005; Nakajima et al., 2011; Hong et al., 2012). Additionally, a three-generation family was reported by Sottas et al. (2013) in which two twin girls suffered sudden cardiac death from their first syncope at ages four and five. Their sister had her first syncope at five months and has a pacemaker. All three sisters are heterozygous for the p.Arg689His variant, as are their mother and maternal grandmother, who have prolonged QT intervals on ECG. The p.Arg689His variant has been found in three of 1,276 healthy controls and is reported at a frequency of 0.000434 in the South Asian population of the Exome Aggregation Consortium. Based on the evidence, the p.Arg689His variant is classified as a variant of unknown significance but suspicious for pathogenicity for SCN5A-related arrhythmias. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000459420 SCV000545033 uncertain significance Brugada syndrome 2018-08-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 689 of the SCN5A protein (p.Arg689His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs199473145, ExAC 0.04%). This variant has been reported in individuals with Brugada syndrome (PMID: 21321465, 28341781), Brugada-like but with no symptoms of heart disease (PMID: 22490985), and arrhythmia (PMID: 15996170, 23692053). This variant has also been reported in individuals with sudden infant death syndrome (PMID: 16453024) and sudden cardiac death in one family (PMID: 23692053). However, it has also been reported in control samples in some studies (PMID: 15851227, 23861362, 23465283). ClinVar contains an entry for this variant (Variation ID: 67710). This variant identified in the SCN5A gene is located in the interdomain linker DI/DII region of the resulting protein (PMID: 25348405). For more information about the location of this variant, please visit www.invitae.com/SCN5A-topology. Experimental evidence shows conflicting results for the ability to generate sodium current in cells transfected with p.Arg689His SCN5A protein (PMID: 22490985, 23692053). In summary, this variant is a rare missense change with uncertain impact on protein function and it has been reported in healthy as well as affected individuals. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000212991 SCV000272409 uncertain significance not specified 2015-08-03 criteria provided, single submitter clinical testing The p.Arg689His variant in SCN5A has been previously reported in 6 individuals w ith arrhythmia (3 with Brugada syndrome, 1 with long QT, 1 with VT and mitral va lvular disease, and 1 with progressive conduction disease and episodes of syncop e; Maekawa 2005, Napolitano 2005, Nakajima 2011, Hong 2012, Sottas 2013). In the family with episodes of syncope, the variant segregated with disease in 2 affec ted siblings who had syncope and sudden death and 2 additional family members wi th borderline QT prolongation (Sottas 2013). However, this variant has also been reported in 7/16128 South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs199473145). In vitro functional studies provide some evidence that the p.Arg689His variant may impact protein fu nction (Hong 2012, Sottas 2013), but these types of assays may not accurately re present biological function. Furthermore, arginine (Arg) at position 689 is not conserved in mammals or evolutionarily distant species, and 7 mammals carry a hi stidine (His) at this position, suggesting that this change may be tolerated. In summary, the clinical significance of the p.Arg689His variant is uncertain.

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