Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV000461521 | SCV000551878 | pathogenic | Seizures, benign familial infantile, 3; Developmental and epileptic encephalopathy, 11 | 2016-08-16 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in SCN2A are known to be pathogenic. This particular variant has been reported in the literature (PMID: 22495306, 24859339). This sequence change creates a premature translational stop signal at codon 959 (p.Cys959*) of the SCN2A gene. It is expected to result in an absent or disrupted protein product. |
Broad Center for Mendelian Genomics, |
RCV002280118 | SCV002568400 | pathogenic | Developmental and epileptic encephalopathy, 11 | 2022-08-25 | criteria provided, single submitter | curation | The heterozygous p.Cys959Ter variant in SCN2A was identified in 1 individual with a neurodevelopmental disorder including autism, global developmental delay, absent speech, and stereotypy via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Neurodev Study (https://www.neurodevproject.org/). Trio exome analysis showed this variant to be de novo. The p.Cys959Ter variant in SCN2A was found to be de novo in 2 individuals with neurodevelopmental disorders (PMID: 22495306, 24859339), and was absent from large population studies. This variant has also been reported in ClinVar (Variation ID#: 410979) and has been interpreted as pathogenic by Invitae and GenomeConnect - Simons Searchlight. In vitro functional studies provide some evidence that the p.Cys959Ter variant may impact protein function (PMID: 28256214). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 959, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the SCN2A gene is an established disease mechanism in neurodevelopmental disorders. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant complex neurodevelopmental disorder. ACMG/AMP Criteria applied: PVS1, PS2_moderate, PM2_supporting, PS3_supporting, PS4_supporting (Richards 2015). |
Genome |
RCV001265278 | SCV001443395 | pathogenic | Complex neurodevelopmental disorder | 2016-06-10 | no assertion criteria provided | provider interpretation | Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2016-06-10 and interpreted as Pathogenic. Variant was initially reported by the University of Washington TIGER study and was later confirmed by GeneDx. The reporting laboratory might also submit to ClinVar. |