ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.5872C>T (p.Arg1958Ter) (rs757532106)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183137 SCV000235550 likely pathogenic not provided 2017-06-30 criteria provided, single submitter clinical testing The R1958X likely pathogenic variant in the SCN5A gene has been reported in one individual with LQTS and in two individuals with borderline QTc intervals (Hedley et al., 2009; Trolle et al., 2013; Chang et al., 2014). In addition, this variant has been observed in other unrelated individuals referred for cardiac genetic testing at GeneDx, and it is classified in ClinVar as a likely pathogenic variant by another clinical laboratory (ClinVar SCV000341424.2; Landrum et al., 2016). The R1958X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). R1958X results in the loss of the last 59 amino acids of the protein and is predicted to cause loss of normal protein function by protein truncation. Although other nonsense variants in the SCN5A gene have been reported in the Human Gene Mutation Database in association with arrhythmia, none have been reported downstream of R1958X (Stenson et al., 2014). Nevertheless, the R1958X variant deletes the PDZ and PY binding motifs of SCN5A protein, which both impact protein expression and function (Shy et al., 2014).
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000183137 SCV000341424 uncertain significance not provided 2018-06-21 criteria provided, single submitter clinical testing
Invitae RCV000701051 SCV000829833 uncertain significance Brugada syndrome 2020-03-05 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the SCN5A gene (p.Arg1958*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 59 amino acids of the SCN5A protein. This variant is present in population databases (rs757532106, ExAC 0.03%). This variant has been observed in several individuals with clinical features of long QT syndrome, dilated cardiomyopathy or unexplained cardiac arrest (PMID: 19862833, 28600387, 27532257, 24388587, 15840476). ClinVar contains an entry for this variant (Variation ID: 201546). Experimental studies and prediction algorithms are not available or were not evaluated for this variant, and the functional significance of the affected amino acid(s) is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics,Fulgent Genetics RCV000763107 SCV000893649 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
Color Health, Inc RCV001184991 SCV001351106 uncertain significance Arrhythmia 2020-09-16 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 28 of the SCN5A gene, creating a premature translation stop signal. This variant occurs in the last exon and may result in a truncated protein product missing the last 59 amino acids of the protein. To our knowledge, functional assays have not been performed for this variant. However, a different truncation variant p.Arg1944* missing the last 73 amino acids of the protein has shown negligible effects on protein expression and function in an experimental study (PMID: 28370132). This variant has been reported in an individual affected with long QT syndrome (PMID: 19862833), in two individuals having borderline long QTc intervals (PMID: 23936059, 24388587), in two individuals with dilated cardiomyopathy (PMID: 27532257, 29961767) and in an individual with unexplained cardiac arrest (PMID: 28600387). This variant has also been identified in 13/276598 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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