Total submissions: 8
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000463355 | SCV000552965 | pathogenic | Spastic paraplegia | 2024-08-10 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 3135 of the SACS protein (p.Leu3135Ser). This variant is present in population databases (rs371019314, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive spastic ataxia of Charlevoix-Saguenay (PMID: 29538656; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 411687). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SACS protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. |
| Athena Diagnostics | RCV000712993 | SCV000843553 | likely pathogenic | not provided | 2022-10-10 | criteria provided, single submitter | clinical testing | The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). In multiple individuals with clinical features associated with this gene, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging. |
| Genome- |
RCV001782958 | SCV002026593 | likely pathogenic | Charlevoix-Saguenay spastic ataxia | 2021-09-05 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001782958 | SCV002511804 | likely pathogenic | Charlevoix-Saguenay spastic ataxia | 2023-05-12 | criteria provided, single submitter | clinical testing | Variant summary: SACS c.9404T>C (p.Leu3135Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 248822 control chromosomes (gnomAD). c.9404T>C has been reported in the literature in individuals affected with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay (Parkinson_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 29538656). Four ClinVar submitters have assessed the variant since 2014: two classified the variant as uncertain significance, one as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Baylor Genetics | RCV001782958 | SCV004209893 | likely pathogenic | Charlevoix-Saguenay spastic ataxia | 2023-11-21 | criteria provided, single submitter | clinical testing | |
| PROSPAX |
RCV001782958 | SCV005044524 | likely pathogenic | Charlevoix-Saguenay spastic ataxia | 2022-01-01 | criteria provided, single submitter | research | |
| Fulgent Genetics, |
RCV001782958 | SCV005634268 | likely pathogenic | Charlevoix-Saguenay spastic ataxia | 2024-03-20 | criteria provided, single submitter | clinical testing | |
| Genome Diagnostics Laboratory, |
RCV001848816 | SCV002105115 | uncertain significance | Hereditary spastic paraplegia | 2017-10-02 | flagged submission | clinical testing |