Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV001584109 | SCV001811164 | uncertain significance | not provided | 2023-09-15 | criteria provided, single submitter | clinical testing | Reported previously in the heterozygous state in a 3 year old male who underwent exome sequencing and was noted to also harbor a pathogenic variant in a different gene (Posey et al., 2017); however, no clinical details were provided and segregation data was unavailable; Missense variants in this gene are often considered pathogenic (HGMD); This substitution is predicted to be in the cytoplasmic loop between the first and second homologous domains; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27959697) |
Invitae | RCV001861452 | SCV002147197 | likely pathogenic | Early infantile epileptic encephalopathy with suppression bursts | 2023-12-30 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 570 of the SCN1A protein (p.Ser570Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SCN1A-related conditions (PMID: 27959697). ClinVar contains an entry for this variant (Variation ID: 374331). 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 with a positive predictive value of 95%. This variant disrupts the p.Ser570 amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28202706, 35074891). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
Ambry Genetics | RCV002402109 | SCV002712255 | uncertain significance | Inborn genetic diseases | 2017-08-25 | criteria provided, single submitter | clinical testing | The p.S570N variant (also known as c.1709G>A), located in coding exon 11 of the SCN1A gene, results from a G to A substitution at nucleotide position 1709. The serine at codon 570 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Baylor Genetics | RCV000415450 | SCV000328811 | uncertain significance | Severe myoclonic epilepsy in infancy; Generalized epilepsy with febrile seizures plus, type 2 | 2015-01-25 | no assertion criteria provided | clinical testing | Our laboratory reported dual molecular diagnoses in SCN1A (NM_001165963.1, c.1709G>A) and PDHA1 (NM_001173454.1, c.292-2A>G) in this individual with features of speech delay and seizure disorder. This variant was paternally inherited from a father with a childhood-onset seizure disorder. |