Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001321927 | SCV001512779 | uncertain significance | Early infantile epileptic encephalopathy with suppression bursts | 2025-01-25 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 364 of the SCN1A protein (p.Ser364Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SCN1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 1022059). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SCN1A protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Victorian Clinical Genetics Services, |
RCV004594272 | SCV005086046 | uncertain significance | Developmental and epileptic encephalopathy, 6 | 2024-09-20 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with SCN1A-related epilepsy (PMID: 28488083). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 20301494). (I) 0115 - Variants in this gene are known to have variable expressivity. Inter-familial and intra-familial variable expressivity has been observed (PMID: 20301494). (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to threonine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. p.(Ser364Ile) has been classified once as likely pathogenic and once as VUS in ClinVar, p.(Ser364Asn) has been classified once as VUS in ClinVar, p.(Ser364Arg) has been classified as likely pathogenic and VUS in ClinVar, and has been observed in two individuals with Dravet syndrome with early onset parkinsonian features (PMID: 28186331). (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. ClinVar contains one VUS entry for this variant, however it is difficult to establish if this entry is related to our patient. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |