ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.283G>A (p.Val95Ile) (rs199473054)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182923 SCV000235318 likely pathogenic not provided 2013-11-07 criteria provided, single submitter clinical testing p.Val95Ile (GTA>ATA): c.283 G>A in exon 3 of the SCN5A gene (NM_198056.2) The Val95Ile variant in the SCN5A gene has been reported previously in one Chinese individual diagnosed with Brugada syndrome, who also harbored the Ala1649Val variant in SCN5A (Liang P et al., 2006). Both variants were inherited from this patient's father who was asymptomatic and had a normal ECG, however, suggesting that V95I may not be pathogenic (Liang P et al., 2006). Additionally, Val95Ile was reported in one individual from a cohort of 120 sudden adult death cases in the Han Chinese (Hou Y et al., 2013). Mutations in nearby residues (Phe93Ser, Ile94Ser, Arg104Gln) have been reported in association with Brugada syndrome, further supporting the functional importance of this region of the protein. Furthermore, the Val95Ile variant was not observed in approximately 6300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, one in vitro functional study showed that this variant does not affect sodium channel function (Gutter C et al., 2013). In summary, Val95Ile is a good candidate for a disease-causing mutation. The variant is found in ARRHYTHMIA panel(s).
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000455416 SCV000540281 uncertain significance not specified 2017-01-10 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in 3 papers in HGMD, classified as DM related to Brugada syndrome. It has been seen in affected and unaffected patients. It is classified in ClinVar with 1 star as Likely Pathogenic by GeneDx (in 2013).
Invitae RCV000058531 SCV000939697 uncertain significance Brugada syndrome 2019-08-23 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 95 of the SCN5A protein (p.Val95Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs199473054, ExAC 0.02%). This variant has been observed in an individual affected with Brugada syndrome (PMID: 20877689). ClinVar contains an entry for this variant (Variation ID: 67761). Experimental studies have found that this missense change does not impact SCN5A channel function (PMID: 23805106). 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.
Mendelics RCV000987244 SCV001136494 uncertain significance Brugada syndrome 1 2019-05-28 criteria provided, single submitter clinical testing
Color RCV001185739 SCV001352006 uncertain significance Arrhythmia 2019-03-17 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058531 SCV000090051 not provided Brugada syndrome no assertion provided literature only This variant has been reported as associated with Brugada syndrome in the following publications (PMID:17081365;PMID:20877689). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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