ClinVar Miner

Submissions for variant NM_015046.7(SETX):c.7139G>A (p.Arg2380Gln)

gnomAD frequency: 0.00001  dbSNP: rs145397619
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV000518213 SCV000615209 uncertain significance not provided 2019-08-08 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000524648 SCV000645283 likely benign Amyotrophic lateral sclerosis type 4; Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 2022-12-19 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV001814998 SCV002061932 uncertain significance not specified 2021-06-16 criteria provided, single submitter clinical testing DNA sequence analysis of the SETX gene demonstrated a sequence change c.7139G>A, in exon 24 that results in an amino acid change, p.Arg2380Gln. This sequence change has been described in three non-Finnish European individuals only in the gnomAD population database (dbSNP rs145397619). This sequence change has been previously described in an individual with ataxia with oculomotor apraxia type 2 (AOA2) however a second variant was not identified (PMID: 19696032). Two other changes affecting the same amino acid residue (p.Arg2380Gly, p.Arg2380Trp) have been reported in the homozygous state in individuals with AOA2 (PMIDs: 19696032, 23111195). The p.Arg2380Gln change affects a highly conserved amino acid residue located in the helicase of the SETX protein and in a region where other pathogenic missense variants have been described. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg2380Gln substitution. Due to the lack of functional studies, the clinical significance of the p.Arg2380Gln change remains unknown at this time.
Revvity Omics, Revvity RCV000518213 SCV003827517 uncertain significance not provided 2022-01-01 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV003233692 SCV003931877 uncertain significance Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 2023-02-08 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV003233693 SCV003931888 uncertain significance Amyotrophic lateral sclerosis type 4 2023-02-08 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000518213 SCV005051115 likely pathogenic not provided 2024-05-01 criteria provided, single submitter clinical testing SETX: PM2, PM3, PM5
PreventionGenetics, part of Exact Sciences RCV004541620 SCV004797213 uncertain significance SETX-related disorder 2023-11-29 no assertion criteria provided clinical testing The SETX c.7139G>A variant is predicted to result in the amino acid substitution p.Arg2380Gln. This variant was reported along with a SETX nonsense variant in two individuals from a family with spinocerebellar ataxia with axonal neuropathy (Family ATX-27, Baviera-Muñoz et al. 2022. PubMed ID: 36530930). This variant was also reported in the heterozygous state in an individual with spinocerebellar ataxia with axonal neuropathy; however, a second plausible causative variant was not identified (Anheim et al. 2009. PubMed ID: 19696032). This variant is reported in 0.0023% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Different nucleotide substitutions affecting the same amino acid (p.Arg2380Gly and p.Arg2380Trp) have been reported in the homozygous state in individuals with spinocerebellar ataxia with axonal neuropathy (Anheim et al. 2009. PubMed ID: 19696032; Hammer et al. 2012. PubMed ID: 23111195). At this time, the clinical significance of the c.7139G>A (p.Arg2380Gln) variant is uncertain due to the absence of conclusive functional and genetic evidence.

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