Submissions for variant NM_015046.7(SETX):c.1391C>T (p.Ser464Leu)

gnomAD frequency: 0.00021  dbSNP: rs200614765

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000262880	SCV000477879	uncertain significance	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000320659	SCV000477880	uncertain significance	Amyotrophic lateral sclerosis type 4	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Athena Diagnostics Inc	RCV002472998	SCV000615156	uncertain significance	not provided	2022-09-28	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools predict that this variant is damaging.
Invitae	RCV000687686	SCV000815271	likely benign	Amyotrophic lateral sclerosis type 4; Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	2024-01-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002392927	SCV002696000	uncertain significance	Inborn genetic diseases	2022-02-28	criteria provided, single submitter	clinical testing	The p.S464L variant (also known as c.1391C>T), located in coding exon 8 of the SETX gene, results from a C to T substitution at nucleotide position 1391. The serine at codon 464 is replaced by leucine, an amino acid with dissimilar properties. The p.S464L alteration was reported in one patient with sporadic amyotrophic lateral sclerosis (ALS) among a cohort of 698 patients, and not seen among 84 cases of familial ALS (Cady J et al. Ann Neurol, 2015 Jan;77:100-13). This amino acid position is well 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.
GeneDx	RCV002472998	SCV004022928	uncertain significance	not provided	2023-07-25	criteria provided, single submitter	clinical testing	Reported in heterozygous state in an individual with sporadic ALS in published literature (Cady et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33333218, 25382069)
PreventionGenetics, part of Exact Sciences	RCV003950295	SCV004761724	uncertain significance	SETX-related condition	2024-01-16	criteria provided, single submitter	clinical testing	The SETX c.1391C>T variant is predicted to result in the amino acid substitution p.Ser464Leu. This variant was reported in an individual with amyotrophic lateral sclerosis (Cady et al. 2015. PubMed ID: 25382069). However, it has also been reported in 0.025% of alleles in individuals of European (Non-Finnish) descent in gnomAD (36 of 250,406 total alleles). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.