ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.5869C>T (p.Arg1957Ter) (rs757532106)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000183137 SCV000341424 uncertain significance not provided 2018-06-21 criteria provided, single submitter clinical testing
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
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).
Invitae RCV000701051 SCV000829833 pathogenic Brugada syndrome 2018-12-19 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 delete the last 59 amino acids of the SCN5A protein. This variant is present in population databases (rs757532106, ExAC 0.03%). This variant has been reported in the literature in an individuals affected with long QT syndrome (PMID: 19862833), dilated cardiomyopathy (PMID: 27532257), in individuals affected with borderline long QT syndrome (PMID: 23936059, 24388587), and in an individual who had an unexplained cardiac arrest (PMID: 28600387). ClinVar contains an entry for this variant (Variation ID: 201546). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acids is currently unknown. Other missense substitutions downstream of this truncation (p.Arg1958Gln and p.Val2016Met) have been reported in individuals affected with SCN5a-related disease (PMID: 15840476, 24895455). For these reasons, this variant has been classified as Pathogenic.

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