ClinVar Miner

Submissions for variant NM_015046.7(SETX):c.991A>G (p.Ile331Val)

gnomAD frequency: 0.00005  dbSNP: rs572884359
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001883640 SCV002140548 benign Amyotrophic lateral sclerosis type 4; Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 2023-11-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV002386648 SCV002694341 uncertain significance Inborn genetic diseases 2023-04-05 criteria provided, single submitter clinical testing Unlikely to be causative of SETX-related juvenile amyotrophic lateral sclerosis (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx RCV002464496 SCV002759127 uncertain significance not provided 2022-11-30 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004770253 SCV005381034 uncertain significance not specified 2024-08-15 criteria provided, single submitter clinical testing Variant summary: SETX c.991A>G (p.Ile331Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-05 in 251420 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SETX causing Amyotrophic Lateral Sclerosis Type 4, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.991A>G in individuals affected with Amyotrophic Lateral Sclerosis Type 4 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1379186). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences RCV004542153 SCV004763623 uncertain significance SETX-related disorder 2023-11-18 no assertion criteria provided clinical testing The SETX c.991A>G variant is predicted to result in the amino acid substitution p.Ile331Val. To our knowledge, this variant has not been reported in the literature. Of note, a different missense variant at the same position (p.Ile331Lys) has been reported in an individual with ataxia with oculomotor apraxia (Nanetti et al. 2013. PubMed ID: 23941260). At this time, the clinical significance of the c.991A>G (p.Ile331Val) variant is uncertain.

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