ClinVar Miner

Submissions for variant NM_015046.7(SETX):c.5332C>T (p.Arg1778Ter)

gnomAD frequency: 0.00001  dbSNP: rs1169623576
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute for Human Genetics and Genomic Medicine, Uniklinik RWTH Aachen RCV001797866 SCV002039193 likely pathogenic Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 2021-12-23 criteria provided, single submitter clinical testing The variant p.(Arg1778*) is present at a very low frequency (gnomAD: 2/251022) in population databases which is in line with autosomal inheritance. Nonsense variants in SETX are known to be pathogenic for the associated autosomal recessive phenotype. The variant is therfore considered to be likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001797866 SCV004029121 pathogenic Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 2023-07-10 criteria provided, single submitter clinical testing Variant summary: SETX c.5332C>T (p.Arg1778X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8e-06 in 251022 control chromosomes. c.5332C>T has been reported in the literature in a homozygous individual affected with Spinocerebellar Ataxia, Autosomal Recessive, With Axonal Neuropathy 2 (Haack_2009). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 19377860). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Neuberg Centre For Genomic Medicine, NCGM RCV001797866 SCV005042583 likely pathogenic Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 criteria provided, single submitter clinical testing The stop gain c.5332C>T p.Arg1778Ter in SETX gene has been reported previously in homozygous state in an individual affected with Ataxia with oculomotor apraxia type 2 Haack et al. 2009. The c.5332C>T variant is reported with an allele frequency of 0.0008% in the gnomAD exomes database and is novel not in any individuals in 1000 Genomes database.This variant has been reported to the ClinVar database as Likely Pathogenic. The nucleotide change c.5332C>T in SETX is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic.

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