Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000188963 | SCV000242594 | uncertain significance | not provided | 2017-09-19 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the SCN1A gene. The P1519T variant has previously reported in an individual with Dravet syndrome, however parental testing was not reported (Moehring et al., 2013). The P1519T variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P1519T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution alters a conserved position predicted to be within the cytoplasmic loop between third and fourth homologous domains. In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. |
Invitae | RCV000818881 | SCV000959518 | pathogenic | Early infantile epileptic encephalopathy with suppression bursts | 2022-06-13 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN1A protein function. ClinVar contains an entry for this variant (Variation ID: 206838). This variant is also known as c.4522C>A (p.Pro1508Thr). This missense change has been observed in individual(s) with SCN1A-related conditions (PMID: 23398550, 33391346; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1519 of the SCN1A protein (p.Pro1519Thr). |
Epilepsy and Neurogenetic Laboratory, |
RCV001254862 | SCV001190015 | likely pathogenic | Generalized epilepsy with febrile seizures plus, type 2 | 2020-02-28 | criteria provided, single submitter | research | The missense variant is identified in a proband presented with Genetic Epilepsy with Febrile Seizure Plus without developmental delay. The variant is inherited from the affected father who also have FS. There are other members in the paternal side known to have FS. According to ACMG guidelines, this variant is classified as likely pathogenic due to PM1: Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation; PM2: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium; PP1: Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease; PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). |
Ambry Genetics | RCV002517889 | SCV003561305 | uncertain significance | Inborn genetic diseases | 2021-06-25 | criteria provided, single submitter | clinical testing | Moehring, 2013; Lindy, 2018 Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |