ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.4245+1G>C (rs794728879)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183065 SCV000235474 pathogenic not provided 2018-09-05 criteria provided, single submitter clinical testing The c.4245+1 G>C pathogenic variant in SCN5A has been reported previously in an individual referred for long QT genetic testing (Lieve et al., 2013). This variant has also been observed in other unrelated individuals referred for Brugada syndrome genetic testing at GeneDx, and segregation with disease was observed in at least two affected relatives in two different families. The c.4245+1 G>C variant destroys the canonical splice donor site of intron 23 and is expected to cause abnormal gene splicing. This variant is predicted to lead to either an abnormal message, which is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.4245+1 G>C variant occurs in the S5 transmembrane helix of homologous domain III, which lines the pore of the NaV1.5 channel and is required for proper channel function. Other downstream splice site variants in the SCN5A gene have been reported in the Human Gene Mutation Database in association with arrhythmia (Stenson et al., 2014). Finally, the c.4245+1 G>C variant was not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server), indicating it is not a common benign variant in these populations. In summary, c.4245+1 G>C in the SCN5A gene is interpreted as a pathogenic variant.
Invitae RCV000558735 SCV000637151 pathogenic Brugada syndrome 2019-11-20 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 23 of the SCN5A gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been reported in the literature in an individual referred for long QT syndrome genetic testing (PMID: 23631430) and in individuals affected with Brugada syndrome (PMID: 28341781, Invitae). ClinVar contains an entry for this variant (Variation ID: 201508). 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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SCN5A are known to be pathogenic (PMID: 20129283, 22789973). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000826183 SCV000967725 likely pathogenic Brugada syndrome; Congenital long QT syndrome 2018-10-23 criteria provided, single submitter clinical testing The c.4245+1G>C variant in SCN5A has been reported in 1 individual referred for long QT syndrome genetic testing (Lieve 2013) and has also been reported by othe r clinical laboratories in ClinVar (Variation ID: 201508). This variant was abse nt from large population studies. This variant occurs within the canonical splic e site (+/- 1,2) and is predicted to cause altered splicing leading to an abnorm al or absent protein. Loss of function variants in SCN5A are most commonly assoc iated with Brugada syndrome although overlap presentations including other SCN5A -related phenotypes (Long QT syndrome) have been described (Remme 2013). In summ ary, although additional studies are required to fully establish its clinical si gnificance, the c.704-2A>G variant is likely pathogenic for Brugada syndrome in an autosomal dominant manner based upon the predicted impact to the protein and absence from the general population. ACMG/AMP Criteria applied: PVS1_Strong, PM2 .

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