Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Variantyx, |
RCV000005591 | SCV007593631 | pathogenic | Spinocerebellar ataxia type 5 | 2025-06-25 | criteria provided, single submitter | clinical testing | This is an inframe substitution variant in the SPTBN2 gene (OMIM: 604985). Pathogenic variants in this gene have been associated with autosomal dominant spinocerebellar ataxia 5. This variant causes an in-frame deletion of 13 amino acids at position 32-44 of the SPTBN2 protein (PM4). It has been reported in at least one affected individual (PMID: 16429157) (PS4 )and shown to segregate with disease in at least 50 individuals from the same family (PMID: 16429157) (PP1). Functional studies have shown that this variant alters SPTBN2 protein function (PMID: 16429157, 25057192, 20368622) (PS3). This variant is absent from control populations (https://gnomad.broadinstitute.org/) (PM2). Based on the current evidence, this variant is classified as pathogenic for autosomal dominant spinocerebellar ataxia 5. |
| Gene |
RCV000518014 | SCV005080825 | pathogenic | not provided | 2023-12-04 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect as this in-frame deletion causes deficits in synapse formation at the neuromuscular junction, disrupts vesicular trafficking, and impacts function and stabilization of key proteins in Purkinje cells (PMID: 25057192, 16429157, 20368622); In-frame deletion of 13 amino acids in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33801522, 25057192, 20368622, 16429157) |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000005591 | SCV002766339 | pathogenic | Spinocerebellar ataxia type 5 | 2022-11-25 | criteria provided, single submitter | clinical testing | Variant summary: SPTBN2 c.1596_1634del39 (p.Glu532_Met544del) results in an in-frame deletion that is predicted to remove 13 amino acids from the encoded protein. The variant was absent in 236106 control chromosomes. c.1596_1634del39 has been reported in the literature in multiple individuals affected with Spinocerebellar Ataxia 5 from a large 11-generation American kindred (example, Ikeda_2006). These data indicate that the variant is very likely to be associated with disease. At two publications report experimental evidence evaluating an impact on protein function demonstrating, 1. disruption of the normal stabilization of the glutamate transporter EAAT4 at the plasma membrane and 2. a mouse model with features consistent to pathophysiology of human disease (example, Ikeda_2006, Armbrust_2014). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Labcorp Genetics |
RCV000518014 | SCV002192274 | pathogenic | not provided | 2024-06-23 | criteria provided, single submitter | clinical testing | This variant, c.1596_1634del, results in the deletion of 13 amino acid(s) of the SPTBN2 protein (p.Glu532_Met544del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with autosomal dominant spinal cerebellar ataxia type 5 (PMID: 16429157). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 448482). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SPTBN2 function (PMID: 25057192). For these reasons, this variant has been classified as Pathogenic. |
| Genetic Services Laboratory, |
RCV000518014 | SCV002069118 | pathogenic | not provided | 2018-02-20 | criteria provided, single submitter | clinical testing | |
| Athena Diagnostics | RCV000518014 | SCV000615452 | pathogenic | not provided | 2022-11-16 | criteria provided, single submitter | clinical testing | This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In multiple families, this variant segregates with spinocerebellar ataxia in an autosomal dominant manner. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies show that this variant interferes with beta-III spectrin stabilization of glutamate transporters and receptors (PMID: 16429157, 20368622, 25057192). |
| OMIM | RCV000005591 | SCV000025773 | pathogenic | Spinocerebellar ataxia type 5 | 2006-02-01 | no assertion criteria provided | literature only |