Total submissions: 10
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Variantyx, |
RCV000054554 | SCV007593632 | pathogenic | Spinocerebellar ataxia type 5 | 2026-01-21 | criteria provided, single submitter | clinical testing | This is a nonsynonymous variant in the SPTBN2 gene (OMIM: 604985). Pathogenic variants in this gene have been associated with autosomal dominant spinocerebellar ataxia 5. This variant likely occurred de novo in the proband and individuals reported in the published literature; however, the possibility of parental germline mosaicism cannot be excluded (PMID: 33318253, 29795474) (PS2). It has been reported in at least 5 unrelated affected individuals (PMID: 25981959, 2914369, 33318253, 29795474) (PS4_Moderate). Functional studies have shown that this variant alters SPTBN2 protein function (PMID: 25981959) (PS3_Moderate) and multiple computational algorithms predict a deleterious effect for this variant (REVEL score: 0.857) (PP3). 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. |
| Center of Human Genetics, |
RCV000054554 | SCV006076608 | pathogenic | Spinocerebellar ataxia type 5 | 2025-01-01 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV004965272 | SCV005508640 | pathogenic | Inborn genetic diseases | 2024-11-12 | criteria provided, single submitter | clinical testing | The c.1438C>T (p.R480W) alteration is located in exon 12 (coding exon 11) of the SPTBN2 gene. This alteration results from a C to T substitution at nucleotide position 1438, causing the arginine (R) at amino acid position 480 to be replaced by a tryptophan (W). The SPTBN2 c.1438C>T alteration was flagged as a low confidence call in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in multiple individuals with features consistent with autosomal dominant SPTBN2-related spinocerebellar ataxia (Parolin Schnekenberg, 2015; Nuovo, 2018; Zonta, 2020). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. |
| Victorian Clinical Genetics Services, |
RCV000054554 | SCV005400449 | pathogenic | Spinocerebellar ataxia type 5 | 2024-10-09 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative is a known mechanism of disease in this gene and is associated with autosomal dominant spinocerebellar ataxia 5 (MIM#600224; PMID: 31617442, 31066025). Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive spinocerebellar ataxia 14 (MIM#615386; PMID: 23236289, 31617442, 31066025). (I) 0108 - This gene is associated with both recessive and dominant disease. Heterozygous missense and in frame deletion variants in SPTBN2 have been associated with autosomal dominant spinocerebellar ataxia type 5 (MIM#600224; PMID: 31617442, 31066025). Biallelic loss of function variants have been associated with autosomal recessive spinocerebellar ataxia 14 (MIM#615386; PMID: 23236289, 31617442, 31066025). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (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 spectrin repeat domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar, as well as a VUS entry. In addition, this variant has been observed in multiple heterozygous individuals with congenital spinocerebellar ataxia, five of which were confirmed to be de novo (ClinVar, DECIPHER, PMID: 33318253, 29795474, 22914369, 25981959). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| Labcorp Genetics |
RCV001568501 | SCV003440331 | pathogenic | not provided | 2024-10-23 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 480 of the SPTBN2 protein (p.Arg480Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant spinocerebellar ataxia (PMID: 22914369, 25981959, 33318253). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 64368). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SPTBN2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SPTBN2 function (PMID: 25981959). For these reasons, this variant has been classified as Pathogenic. |
| Gene |
RCV001568501 | SCV001792384 | pathogenic | not provided | 2021-12-23 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29196973, 25142508, 22914369, 31066025, 25981959, 31617442, 30898343, 29795474, 28636205, 31721007, 30167849, 23838597, 29795473, 33084218, 31785789, 33318253, 26821241) |
| Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, |
RCV000054554 | SCV001519211 | pathogenic | Spinocerebellar ataxia type 5 | 2021-01-04 | criteria provided, single submitter | research | |
| Consultorio y Laboratorio de Neurogenética, |
RCV000054554 | SCV001424336 | uncertain significance | Spinocerebellar ataxia type 5 | criteria provided, single submitter | clinical testing | ||
| Mendelics | RCV000054554 | SCV001138354 | pathogenic | Spinocerebellar ataxia type 5 | 2019-05-28 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000054554 | SCV000083033 | pathogenic | Spinocerebellar ataxia type 5 | 2013-10-01 | no assertion criteria provided | literature only |