Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV004790104 | SCV005400063 | pathogenic | Mirror movements 1 | 2023-07-17 | 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: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with gaze palsy, familial horizontal, with progressive scoliosis, 2 (MIM#617542) and mirror movements 1 and/or agenesis of the corpus callosum (MIM#157600). (I) 0108 - This gene is associated with both recessive and dominant disease. Biallelic loss of function variants cause autosomal recessive gaze palsy, familial horizontal, with progressive scoliosis, 2 (MIM#617542) while monoallelic loss of function variants cause the less severe autosomal dominant mirror movements 1 and/or agenesis of the corpus callosum (MIM#157600; PMIDs: 33141514, 31697046). (I) 0112 - The condition associated with this gene has incomplete penetrance. The penetrance for mirror movements is estimated to be approximately 42% (PMID: 25763452) while agenesis of the corpus callosum is 26% (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial variability has been reported for autosomal dominant mirror movements 1 and/or agenesis of the corpus callosum (MIM#157600). Specifically, males tend to present with mirror movements without agenesis of the corpus callosum (ACC) while females are more likely to present with isolated ACC (PMIDs: 25763452, 31697046). (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) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (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) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed) (by segregation analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |