Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ce |
RCV000658864 | SCV000780661 | uncertain significance | not provided | 2018-02-01 | criteria provided, single submitter | clinical testing | |
| Laboratory of Medical Genetics, |
RCV001729680 | SCV001976987 | pathogenic | Hereditary spastic paraplegia 4 | 2021-10-01 | criteria provided, single submitter | clinical testing | PM1, PM2, PP3, PP4, PP5 |
| Labcorp Genetics |
RCV001729680 | SCV002316669 | pathogenic | Hereditary spastic paraplegia 4 | 2022-04-06 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 9, but is expected to preserve the integrity of the reading-frame (PMID: 33638609). ClinVar contains an entry for this variant (Variation ID: 546862). This variant has been observed in individuals with clinical features of hereditary spastic paraplegia (PMID: 22552817, 30476002, 33638609, 34008892; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 9 of the SPAST gene. It does not directly change the encoded amino acid sequence of the SPAST protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. |
| Victorian Clinical Genetics Services, |
RCV001729680 | SCV002557460 | pathogenic | Hereditary spastic paraplegia 4 | 2020-05-25 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. Multiple premature termination codon variants resulting in loss of function have been reported whilst a missense variant has been shown to have gain of function effects (ClinVar; PMID 24478365; PMID 30520996). (N) 0104 - Dominant Negative is a mechanism of disease for this gene for other missense variants (PMID 30006150). (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0112 - Variants in this gene are known to have reduced penetrance (PMID 30476002). (N) 0212 - Non-canonical splice variant without proven consequence on splicing (no functional evidence available) (intron 9 of 16). (P) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (P) 0702 - Comparable variants have strong previous evidence for pathogenicity. Multiple non-canonical splice variants within the same donor region have previously been reported in clinical cases (ClinVar; PMID 22552817; PMID 24648003; PMID 11309678). (P) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times in association with hereditary spastic paraplegia (ClinVar; PMID 27260292; PMID 22552817; PMID 28572275). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign |
| Solve- |
RCV001729680 | SCV005091381 | likely pathogenic | Hereditary spastic paraplegia 4 | 2022-06-01 | no assertion criteria provided | provider interpretation | Variant confirmed as disease-causing by referring clinical team |