ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.998+5G>A (rs187531872)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000252811 SCV000320385 uncertain significance Cardiovascular phenotype 2017-03-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Blueprint Genetics RCV000157496 SCV000207241 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2015-01-29 criteria provided, single submitter clinical testing
Invitae RCV000638693 SCV000760233 uncertain significance Brugada syndrome 2018-01-30 criteria provided, single submitter clinical testing This sequence change falls in intron 8 of the SCN5A gene. It does not directly change the encoded amino acid sequence of the SCN5A protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs187531872, ExAC 0.1%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with long QT syndrome (PMID: 23631430). ClinVar contains an entry for this variant (Variation ID: 165158). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000151802 SCV000200265 uncertain significance not specified 2013-08-15 criteria provided, single submitter clinical testing The 998+5G>A variant in SCN5A has not been reported in individuals with cardiomy opathy, but it has been identified in 1/8366 of European American chromosomes by the NHLBI Exome Sequencing Project and in 0.5% (1/186) of Finnish chromosomes b y the 1000 Genomes Project (;dbSNP rs187531872) . This variant is located in the 5' splice region. Computational tools suggest a possible impact to splicing. However, this information is not predictive enoug h to determine pathogenicity. Additional information is needed to fully assess t he clinical significance of the 998+5G>A variant. 998+5G>A intron 8 of SCN5A (r s187531872; allele frequency = 1/8366) **

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