ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.5827C>T (p.Arg1943Ter) (rs794728940)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183202 SCV000235621 likely pathogenic not provided 2018-09-19 criteria provided, single submitter clinical testing The R1944X likely pathogenic variant in the SCN5A gene has been reported previously in association with sudden unexplained death (SUD); however, this patient also harbored an additional variant in the SCN5A gene and no segregation data was reported (Wang et al., 2014). The R1944X likely pathogenic variant is not observed at any significant frequency in large population cohorts (Lek et al., 2016). Moreover, the R1944X variant is predicted to cause loss of normal protein function by protein truncation with loss of the last 73 amino acids of the protein. Furthermore, one other downstream nonsense pathogenic variant in the SCN5A gene has been reported in the Human Gene Mutation Database in association with arrhythmia (Stenson et al., 2014), and loss-of-function is a known mechanism of disease for the SCN5A gene. In summary, R1944X in the SCN5A gene is interpreted as a likely pathogenic variant.
GenomeConnect, ClinGen RCV000844965 SCV000986790 not provided SCN5A-related disorder no assertion provided phenotyping only Variant interpretted as Likely pathogenic and reported on 03/29/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Illumina Clinical Services Laboratory,Illumina RCV000363289 SCV000443892 uncertain significance SCN5A-Related Disorders 2017-04-28 criteria provided, single submitter clinical testing The SCN5A c.5830C>T (p.Arg1944Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The p.Arg1944Ter variant has been reported in a compound heterozygous state with a missense variant in one individual with sudden death (Wang et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.000014 in the Total population of the Genome Aggregation Database. This variant is located in the last exon and may escape nonsense-mediated decay. The evidence for the p.Arg1944Ter variant is limited. Therefore, due to the potential impact of stop-gained variants and the limited evidence, the p.Arg1944Ter variant is classified as a variant of unknown significance but suspicious for pathogenicity for SCN5A-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000812407 SCV000952718 pathogenic Brugada syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the SCN5A gene (p.Arg1944*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 73 amino acids of the SCN5A protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an infant who suffered sudden unexplained death (PMID: 24631775, 29247119). ClinVar contains an entry for this variant (Variation ID: 201596). This variant disrupts the C-terminus of the SCN5A protein. Other variant(s) that disrupt this region (p.Arg1958*, p.Tyr1995*) have been determined to be pathogenic (PMID: 19862833, 23936059, 24388587, Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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