ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.3068G>A (p.Arg1023His) (rs199473592)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000757741 SCV000235431 uncertain significance not provided 2015-11-16 criteria provided, single submitter clinical testing The R1023H variant in the SCN5A gene has been reported in at least three individuals with arrhythmia or arrhythmic events (Frustaci et al., 2005; Watanabe et al., 2013; Fernandes et al., 2015). Additionally, it has been seen in multiple individuals referred to GeneDx for genetic testing of arrhythmia. Frustaci et al. (2005) identified this variant in an individual with Brugada syndrome with no suspicious family history. Watanabe et al. (2013) and Fernandes et al. (2015) observed the variant in individuals with recorded ventricular fibrillation and ventricular tachycardia, respectively. The proband in Fernandes et al. (2015) harbored two additional variants in arrhythmia-associated genes and had a family history of sudden death. The relative's autopsy showed evidence of chronic ischemic heart disease (Fernandes et al., 2015). Frusaci et al. (2005) and Watanabe et al. (2013) collectively, did not observe R1023H in up to 1200 control alleles. Nevertheless, this variant has been observed in 35/16192 alleles (0.2%) from individuals of South Asian ancestry in the Exome Aggregation Consortium. The R1023H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. In silico analysis predicts this variant likely does not alter the protein structure/function. Finally, Frustaci et al. (2005) and Hoshi et al. (2014) performed functional in vitro studies for R1023H which exhibited biophysical differences in comparison to wild type, however, it was noted that the effect may not be sufficient to cause disease.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000058546 SCV000291794 likely benign Brugada syndrome 2019-12-31 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000183023 SCV000540284 uncertain significance not specified 2016-08-12 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 Brugada proband; also 1 paper reporting functional impact; However, frequency high for disorder; ClinVar: P by GeneDx
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000757741 SCV000886080 uncertain significance not provided 2018-01-23 criteria provided, single submitter clinical testing
Mendelics RCV000987212 SCV001136461 uncertain significance Brugada syndrome 1 2019-05-28 criteria provided, single submitter clinical testing
Color RCV001189665 SCV001356998 likely benign Arrhythmia 2018-11-11 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000183023 SCV001363140 likely benign not specified 2019-01-28 criteria provided, single submitter clinical testing Variant summary: SCN5A c.3068G>A (p.Arg1023His) results in a non-conservative amino acid change located in the Sodium ion transport-associated domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 275816 control chromosomes. The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Arrhythmia phenotype (0.0001), suggesting that the variant may be benign. c.3068G>A has been reported in the literature in at least one individual affected with Arrhythmia (Frustaci_2005). This report does not provide unequivocal conclusions about association of the variant with Arrhythmia. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal activity as measured by voltage gated sodium current density (Frustaci_2005, Hoshi_2014). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, one of whom have classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058546 SCV000090066 not provided Brugada syndrome no assertion provided literature only This variant has been reported as associated with Brugada syndrome in the following publications (PMID:16344400). 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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