Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV004790107 | SCV005400072 | likely pathogenic | Spinocerebellar ataxia 48 | 2022-06-24 | 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: 0103 - Dominant negative and loss of function are suggested mechanisms of disease in this gene and are associated with spinocerebellar ataxia 48 (SCA48; MIM#618093) and spinocerebellar ataxia 16 (MIM#615768), respectively (PMID: 34565360). (I) 0108 - This gene is associated with both recessive and dominant disease. Monoallelic variants have been reported to result in SCA48, whereas biallelic variants have been associated with SCA16 (PMID: 34565360). However, it remains unclear why p.(Arg241Trp) and p.(Cys232Gly) have been associated with both phenotypes (PMID: 33417001). (I) 0115 - Variants in this gene are known to have variable expressivity. There is interfamilial and intrafamilial variability of both severity and features (PMID: 33417001). (I) 0207 - Variant is predicted to result in a loss of the canonical translation initiation codon (ATG) but an alternative initiation codon is known to exist. This downstream start codon (p.Met73) is utilised as the start codon of NM_001293197.2 (UCSC). (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0704 - Another start-loss variant comparable to the one identified in this case has limited previous evidence for pathogenicity. This variant (c.3G>A) has been reported as de novo in an individual with symptoms including cerebellar ataxia and atrophy, myoclonus and mild spasticity (PMID: 33564152, PMID: 33811518). Another comparable variant (c.1A>G) has been reported as a VUS (LOVD). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant has been reported in a heterozygous individual with cognitive decline and cerebellar ataxia, who was also heterozygous for a 44-glutamine repeat in the TBP gene (PMID: 34906452). (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) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |