ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.4556C>T (p.Pro1519Leu) (rs372425457)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188964 SCV000242595 likely pathogenic not provided 2015-10-20 criteria provided, single submitter clinical testing p.Pro1519Leu (CCG>CTG): c.4556 C>T in exon 24 of the SCN1A gene (NM_001165963.1) The P1519L variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. However, a different amino acid substitution at this position (P1519T) has been reported previously in an individual with generalized tonic-clonic seizures and complex partial seizures starting at 12 months of age and mild mental retardation, although information about parental testing was not provided (Moehring et al., 2013). The P1519L variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The P1519L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution alters a highly conserved position in the predicted cytoplasmic loop between third and fourth homologous domains of the SCN1A protein. Additionally, several missense mutations in nearby residues (M1511K, L1514S, I1523T) have been reported in association with SCN1A- related disorders, supporting the functional importance of this region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in EPILEPSY panel(s).
Ambry Genetics RCV000720860 SCV000851744 benign History of neurodevelopmental disorder 2019-05-13 criteria provided, single submitter clinical testing Subpopulation frequency in support of benign classification
Invitae RCV001085148 SCV001015944 likely benign Early infantile epileptic encephalopathy 2019-12-31 criteria provided, single submitter clinical testing
Mendelics RCV000986876 SCV001136024 uncertain significance Severe myoclonic epilepsy in infancy 2019-05-28 criteria provided, single submitter clinical testing

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