Submissions for variant NM_015046.7(SETX):c.2750T>C (p.Met917Thr)

gnomAD frequency: 0.00009  dbSNP: rs376022544

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000713201	SCV000843787	uncertain significance	not provided	2017-11-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000713201	SCV001155787	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	SETX: BP4
Labcorp Genetics (formerly Invitae), Labcorp	RCV001042487	SCV001206169	likely benign	Amyotrophic lateral sclerosis type 4; Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	2024-03-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000713201	SCV002540553	uncertain significance	not provided	2023-09-14	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25382069, 32028661, 32397312)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265868	SCV002548512	uncertain significance	not specified	2022-05-01	criteria provided, single submitter	clinical testing	Variant summary: SETX c.2750T>C (p.Met917Thr) 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 9.6e-05 in 250972 control chromosomes. This frequency does not allow conclusions about variant significance. c.2750T>C has been reported in the literature in settings of multigene panel testing among cohorts with sporadic or a not-specified form of Amyotrophic Lateral Sclerosis (example, Cady_2015, Scarlino_2020, Pensato_2020) and in unaffected non-neurological controls (example, Scarlino_2020). These report(s) do 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002440565	SCV002750599	uncertain significance	Inborn genetic diseases	2020-08-11	criteria provided, single submitter	clinical testing	The p.M917T variant (also known as c.2750T>C), located in coding exon 8 of the SETX gene, results from a T to C substitution at nucleotide position 2750. The methionine at codon 917 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the supporting evidence, this variant is unlikely to be causative of autosomal dominant juvenile amyotrophic lateral sclerosis 4; however, its contribution to the development of autosomal recessive spinocerebellar ataxia with axonal neuropathy 2 is uncertain.
PreventionGenetics, part of Exact Sciences	RCV004535770	SCV004120286	uncertain significance	SETX-related disorder	2022-09-20	criteria provided, single submitter	clinical testing	The SETX c.2750T>C variant is predicted to result in the amino acid substitution p.Met917Thr. This variant was reported in two individuals with amyotrophic lateral sclerosis (Cady et al. 2015. PubMed ID: 25382069; Pensato et al. 2020. PubMed ID: 32028661). This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-135204235-A-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.