Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV002471885 | SCV002767499 | likely pathogenic | Intellectual disability, autosomal dominant 45 | 2022-03-31 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal dominant intellectual disability 45 (MIM# 617600). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Phenotypic variations have been observed among patients (PMIDs: 28288114, 32820034). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0219 - This variant is non-coding in alternative transcripts including NM_015125.5. However it is coding in NM_001304815.1, and NM_001386298.1 which is the ClinVar-predominant and MANE Select transcript. Publicly available gene expression data showed our exon of interest is expressed in human tissues (GTEx), consistent with the western blot data of fibroblast samples in PMID: 28288114. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0704 - Another premature termination variant comparable to the one identified in this case has limited previous evidence for pathogenicity. An NMD-predicted variant in our transcript of interest (p.(Lys496Valfs*57)) has been reported as likely pathogenic in an individual with intellectual disability, autism and anxiety (DECIPHER). (SP) 0807 - This variant has no previous evidence of pathogenicity. (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 |