ClinVar Miner

Submissions for variant NM_001103.3(ACTN2):c.250C>T (p.Leu84=) (rs1558232391)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786215 SCV000924938 uncertain significance not provided 2016-08-03 no assertion criteria provided provider interpretation p.Arg84Cys (c.250C>T) in exon 3 of the SCN2A gene (NM_004588.4) Given the lack of gene level evidence linking SCN2B to the patients phenotype and lack of case data for this variant, we consider this variant to be of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). We have seen this variant in an individual with LVNC. Testing was ordered from Invitae. Per the Invitae report, "The SCN2B gene currently has no well-established disease association; however there is preliminary evidence supporting a correlation with autosomal dominant Brugada syndrome (BrS) (PMID: 23559163) and atrial fibrillation (MedGen UID: 334469)." The variant has not been reported in the literature and is not listed in ClinVar as of 8/3/2016. Per the Invitae report, "this sequence change replaces arginine with cysteine at codon 84 of the SCN2B protein (p.Arg84Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine." The variant was reported online in 6 of 60,471 (0.03%) individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 8/3/2016). Specifically, the variant was observed in 3 of 4,323 East Asian people, 1 of 5,776 Latino people, 1 of 8,252 South Asian people, and 1 of 33,221 non-Finnish European people. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012).

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