ClinVar Miner

Submissions for variant NM_015046.7(SETX):c.1869A>C (p.Glu623Asp)

gnomAD frequency: 0.00015  dbSNP: rs139200312
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000794428 SCV000933834 benign Amyotrophic lateral sclerosis type 4; Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 2023-12-01 criteria provided, single submitter clinical testing
Athena Diagnostics RCV000143814 SCV001145536 uncertain significance not provided 2018-09-12 criteria provided, single submitter clinical testing
GeneDx RCV000143814 SCV002032571 uncertain significance not provided 2021-12-07 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Identified in a patient with amyotrophic lateral sclerosis in published literature, although additional clinical information and familial segregation information were not included (Cady et al., 2015); This variant is associated with the following publications: (PMID: 33333218, 25382069)
Ambry Genetics RCV002408640 SCV002723162 uncertain significance Inborn genetic diseases 2021-04-23 criteria provided, single submitter clinical testing The p.E623D variant (also known as c.1869A>C), located in coding exon 8 of the SETX gene, results from an A to C substitution at nucleotide position 1869. The glutamic acid at codon 623 is replaced by aspartic acid, an amino acid with highly similar properties. Among a cohort of 391 patients with amyotrophic lateral sclerosis (ALS), this alteration was reported in one patient with sporadic ALS but was also present in population databases (Cady J et al. Ann Neurol, 2015 Jan;77:100-13). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this variant is unlikely to be causative of juvenile amyotrophic lateral sclerosis 4 (ALS4); however, its contribution to the development of spinocerebellar ataxia with axonal neuropathy 2 (SCAN2) is uncertain.
CeGaT Center for Human Genetics Tuebingen RCV000143814 SCV004811701 uncertain significance not provided 2024-03-01 criteria provided, single submitter clinical testing
Breakthrough Genomics, Breakthrough Genomics RCV000143814 SCV005190544 uncertain significance not provided criteria provided, single submitter not provided
Northcott Neuroscience Laboratory, ANZAC Research Institute RCV000143814 SCV000188707 non-pathogenic not provided no assertion criteria provided not provided Converted during submission to Benign.
PreventionGenetics, part of Exact Sciences RCV004544322 SCV004768627 uncertain significance SETX-related disorder 2024-04-04 no assertion criteria provided clinical testing The SETX c.1869A>C variant is predicted to result in the amino acid substitution p.Glu623Asp. This variant was reported in one individual with amyotrophic lateral sclerosis (Table 2, Cady et al. 2015. PubMed ID: 25382069). This variant is reported in 0.024% of alleles in individuals of European (non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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