ClinVar Miner

Submissions for variant NM_001040142.2(SCN2A):c.1904T>C (p.Leu635Pro)

gnomAD frequency: 0.00001  dbSNP: rs558887330
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189222 SCV000242854 uncertain significance not provided 2018-04-19 criteria provided, single submitter clinical testing p.Leu635Pro (CTC>CCC): c.1904 T>C in exon 12 of the SCN2A gene (NM_021007.2). A variant of unknown significance has been identified in the SCN2A gene. The L635P 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 L635P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, this substitution alters a poorly conserved position in the cytoplasmic loop between the first and second homologous domains of the SCN2A protein (Shi et al, 2012), and Proline is observed at this position in evolution. 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 EPILEPSYV2-1 panel(s).
Labcorp Genetics (formerly Invitae), Labcorp RCV002517896 SCV001129809 likely benign Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11 2024-02-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV002408848 SCV002722665 likely benign Inborn genetic diseases 2020-01-24 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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