Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Center For Human Genetics And Laboratory Diagnostics, |
RCV001002798 | SCV001160771 | likely pathogenic | Developmental and epileptic encephalopathy, 7 | 2019-09-12 | criteria provided, single submitter | clinical testing | |
| Victorian Clinical Genetics Services, |
RCV001002798 | SCV002557729 | pathogenic | Developmental and epileptic encephalopathy, 7 | 2022-02-02 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with developmental and epileptic encephalopathy 7 (DEE; MIM#613720) and benign neonatal seizures, 1 (BNS; MIM#121200). Missense variants have been reported with a dominant negative mechanism (OMIM, PMID: 24318194) and in patients with either condition. Truncating variants and those predicted to undergo nonsense-mediated decay, have been reported to cause loss of function (DECIPHER) and are almost exclusively found in patients with BNS (PMID: 32917465). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance, however, this is only reported for patients with BNS (PMID: 25959266). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine 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) 0601 - Variant is located in the well-established functional ion transporter domain (NCBI, DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. This alternative change (p.(Ala317Val)), has been reported as de novo and likely pathogenic in an individual with features including global developmental delay and seizures (DECIPHER). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic and de novo in an individual with epileptic encephalopathy (ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |