ClinVar Miner

Submissions for variant NM_006514.3(SCN10A):c.5539C>T (p.Arg1847Ter) (rs199503439)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523173 SCV000620824 uncertain significance not provided 2018-07-12 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN10A gene. The R1847X variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is also not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R1847X variant occurs within the last exon of the SCN10A gene and is predicted to result in a truncated protein due to the loss of the last 110 amino acids of the SCN10A protein. However, no downstream truncating variants in the SCN10A gene have been reported in HGMD in association with SCN10A-related disorders, and the majority of pathogenic variants in the SCN10A gene are missense changes (Stenson et al., 2014), indicating haploinsufficiency of SCN10A may not be sufficient to cause arrhythmia. Furthermore, in the absence of functional expression studies, the physiological consequence of this variant cannot be precisely determined.
Invitae RCV000799130 SCV000938779 uncertain significance Brugada syndrome 2018-12-05 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the SCN10A gene (p.Arg1847*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 110 amino acids of the SCN10A protein. This variant is present in population databases (rs199503439, ExAC 0.01%). This variant has not been reported in the literature in individuals with SCN10A-related conditions. ClinVar contains an entry for this variant (Variation ID: 452050). Experimental studies and prediction algorithms are not available 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.

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