ClinVar Miner

Submissions for variant NM_015046.7(SETX):c.2921T>C (p.Ile974Thr)

gnomAD frequency: 0.00002  dbSNP: rs765768857
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001367523 SCV001563876 benign Amyotrophic lateral sclerosis type 4; Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 2022-11-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV003246955 SCV003938465 uncertain significance Inborn genetic diseases 2023-04-05 criteria provided, single submitter clinical testing The c.2921T>C (p.I974T) alteration is located in exon 10 (coding exon 8) of the SETX gene. This alteration results from a T to C substitution at nucleotide position 2921, causing the isoleucine (I) at amino acid position 974 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003388005 SCV004100172 uncertain significance not specified 2023-09-26 criteria provided, single submitter clinical testing Variant summary: SETX c.2921T>C (p.Ile974Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 250652 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2921T>C has been reported in the literature in at least one individual affected with Amyotrophic Lateral Sclerosis (Couthouis_2014). The report does not provide unequivocal conclusions about association of the variant with Amyotrophic Lateral Sclerosis Type 4. 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: 25299611). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as benign, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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