Submissions for variant NM_015046.7(SETX):c.4612C>T (p.Arg1538Trp)

gnomAD frequency: 0.00035  dbSNP: rs147018359

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000348389	SCV000477826	uncertain significance	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	2018-01-12	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	RCV000400900	SCV000477827	uncertain significance	Amyotrophic lateral sclerosis type 4	2018-01-12	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	RCV003482252	SCV000615190	benign	not provided	2022-06-07	criteria provided, single submitter	clinical testing
Invitae	RCV000644810	SCV000766525	likely benign	Amyotrophic lateral sclerosis type 4; Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	2023-12-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002338959	SCV002639074	uncertain significance	Inborn genetic diseases	2021-03-30	criteria provided, single submitter	clinical testing	The p.R1538W variant (also known as c.4612C>T), located in coding exon 8 of the SETX gene, results from a C to T substitution at nucleotide position 4612. The arginine at codon 1538 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration was detected in two patients among an ALS cohort (Scarlino S et al. Int J Mol Sci, 2020 May;21:). This amino acid position is poorly 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	RCV003972539	SCV004789650	likely benign	SETX-related condition	2023-04-27	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).