ClinVar Miner

Submissions for variant NM_001040142.2(SCN2A):c.2674G>A (p.Val892Ile) (rs121917751)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189121 SCV000242753 pathogenic not provided 2013-09-10 criteria provided, single submitter clinical testing The Val892Ile missense substitution was previously reported to segregate with benign familial neonatal-infantile seizures (BFNIS) in multiple members of a single large family (Berkovic et al., 2004). This amino acid subsitution 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. It is a conservative amino acid, as Valine and Isoleucine are both uncharged, non-polar amino acids; however, it alters a conserved position in the S5 segment of the second transmembrane domain. Therefore, Val892Ile is considered a disease-causing mutation. The variant is found in EPILEPSY panel(s).
Invitae RCV000527590 SCV000639618 pathogenic Benign familial neonatal-infantile seizures; Early infantile epileptic encephalopathy 11 2018-05-24 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 892 of the SCN2A protein (p.Val892Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with benign familial neonatal-infantile seizures in several families with multiple affected individuals (PMID: 15048894, 29215089). ClinVar contains an entry for this variant (Variation ID: 15048894). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000527590 SCV000898955 likely pathogenic Benign familial neonatal-infantile seizures; Early infantile epileptic encephalopathy 11 2018-08-15 criteria provided, single submitter clinical testing SCN2A NM_021007.2 exon 16 p.Val892Ile (c.2674G>A): This variant has been reported in the literature in at least 2 individuals with Benign Familial Neonatal-Infantile Epilepsy (BFNIE), segregating with disease in at least 5 affected family members (Berkovic 2004 PMID:15048894, Zeng 2018 PMID:29215089). This variant is not present in large control databases. This variant is present in ClinVar (Variation ID:12878). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic.
OMIM RCV000013738 SCV000033985 pathogenic Benign familial neonatal-infantile seizures 2004-04-01 no assertion criteria provided literature only

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