Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Molecular Genetics, |
RCV002225177 | SCV002503708 | uncertain significance | Spinocerebellar ataxia 48 | 2021-07-02 | criteria provided, single submitter | clinical testing | This sequence change is predicted to replace glycine with valine at codon 249 of the STUB1 protein (p.(Gly249Val)). The glycine residue is evolutionarily conserved (100 vertebrates, UCSC), and located in the ubiquitin ligase (U-box) domain (UniProt). There is a large physicochemical difference between glycine and valine. The variant is absent in a large population cohort (gnomAD v2.1). In vitro functional assays demonstrated that the variant impaired ubiquitination activity on the Hsc70 substrate and inability to perform self-ubiquitination (PMID: 34070858). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.4.0, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PS3_Supporting, PM2_Supporting, PP3. |
| Victorian Clinical Genetics Services, |
RCV004785533 | SCV005399287 | uncertain significance | Autosomal recessive spinocerebellar ataxia 16 | 2022-02-02 | 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 - 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 inter- and intrafamilial variability of both severity and features (PMID: 33417001). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to valine. (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) 0600 - Variant is located in the annotated U-box domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. However, this family has been reported by Pakdaman, Y. et al. (2021) with a history of dementia and this proband was diagnosed with SCA48 (PMID: 34070858). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Mutagenesis studies showed mutant allele impaired ubiquitination and self-ubiquitination activity. In addition, mutant resulted in a lack of dimers compared to wild-type with a consequent accumulation of aggregates (PMID: 34070858). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |