Submissions for variant NM_015046.7(SETX):c.1468G>A (p.Val490Ile)

gnomAD frequency: 0.00004  dbSNP: rs763545230

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000700292	SCV000829040	uncertain significance	Amyotrophic lateral sclerosis type 4; Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	2022-01-02	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 577511). This missense change has been observed in individual(s) with hereditary sensory neuropathy (PMID: 28708278). This variant is present in population databases (rs763545230, gnomAD 0.006%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 490 of the SETX protein (p.Val490Ile).
Athena Diagnostics Inc	RCV000713198	SCV000843784	uncertain significance	not provided	2018-02-14	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000713198	SCV001155789	uncertain significance	not provided	2016-06-01	criteria provided, single submitter	clinical testing
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	RCV001644767	SCV001519250	uncertain significance	Spastic ataxia	2021-01-04	criteria provided, single submitter	research
GeneDx	RCV000713198	SCV002546609	uncertain significance	not provided	2022-07-05	criteria provided, single submitter	clinical testing	Reported previously as a variant of uncertain significance in a patient with axonal nerve conduction study findings, ataxia, dysarthria, and nystagmus; however, no segregation information was provided (Hartley et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28708278)
Ambry Genetics	RCV002388306	SCV002701261	uncertain significance	Inborn genetic diseases	2021-07-14	criteria provided, single submitter	clinical testing	The p.V490I variant (also known as c.1468G>A), located in coding exon 8 of the SETX gene, results from a G to A substitution at nucleotide position 1468. The valine at codon 490 is replaced by isoleucine, an amino acid with highly similar properties. This variant was detected in an individual with hereditary sensory neuropathy; however, clinical details were limited (Hartley T et al. Clin Genet, 2018 02;93:301-309). This amino acid position is highly 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 amyotrophic lateral sclerosis 4 (ALS4); however, its contribution to the development of spinocerebellar ataxia with axonal neuropathy 2 (SCAN2) is uncertain.
Genome-Nilou Lab	RCV003233822	SCV003931548	uncertain significance	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003233823	SCV003931549	uncertain significance	Amyotrophic lateral sclerosis type 4	2023-02-08	criteria provided, single submitter	clinical testing