ClinVar Miner

Submissions for variant NM_001040142.2(SCN2A):c.1729C>A (p.Leu577Ile) (rs796053187)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189218 SCV000242850 uncertain significance not provided 2016-11-03 criteria provided, single submitter clinical testing p.Leu577Ile (CTT>ATT): c.1729 C>A in exon 12 of the SCN2A gene (NM_021007.2). A variant of unknown significance has been identified in the SCN2A gene. The L577I variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L577I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution alters a conserved position in the cytoplasmic loop between the first and second homologous domains of the SCN2A protein (Shi et al., 2012), although Isoleucine is observed at this position in multiple species in distant evolution. A missense mutation in a nearby residue (A575V) has been reported in association with a SCN2A-related disorder. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).

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