Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000793389 | SCV000932738 | likely pathogenic | Hereditary spastic paraplegia 31 | 2018-12-18 | criteria provided, single submitter | clinical testing | Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in REEP1 are known to be pathogenic (PMID: 18321925, 18644145). This variant has not been reported in the literature in individuals with REEP1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 1 of the REEP1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. |
| Victorian Clinical Genetics Services, |
RCV000793389 | SCV002767458 | likely pathogenic | Hereditary spastic paraplegia 31 | 2021-05-06 | 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 spastic paraplegia 31 (MIM#610250) and distal neuronopathy hereditary motor, type VB (MIM#614751) (PMID: 29124833, PMID: 22703882). (I) 0107 - This gene is associated with autosomal dominant disease (OMIM). However, recent reports have described two families with autosomal recessive disease, where carrier parents were either healthy, or not fully neurologically assessed (PMID: 31872057, PMID: 27066569). (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). While evidence of altered splicing has been described in a thesis, this finding has not been peer reviewed in a publication (Meszarosova, 2018). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0311 - An alternative nucleotide change at the same canonical splice region, is present in gnomAD (v2, v3) (1 heterozygote, 0 homozygotes). (I) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0705 - No comparable canonical splice variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic, and observed once in a large cohort of individuals with a neurological and developmental disorder (PMID: 32581362, ClinVar). This variant has also observed in a family with spastic paraplegia. However, this family has only been described in a thesis and the findings have not been peer reviewed in a publication (Meszarosova, 2018). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been observed in multiple affected individuals within this family, and was also absent in two unaffected relatives (LABID). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant is assumed to be paternally inherited due to a paternal history of the disorder and at least one tthese relatives being shown to have this variant. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| NIHR Bioresource Rare Diseases, |
RCV001003952 | SCV001161942 | likely pathogenic | Spastic paraplegia | no assertion criteria provided | research |