Submissions for variant NM_015046.7(SETX):c.6122T>C (p.Ile2041Thr)

gnomAD frequency: 0.00004  dbSNP: rs140676924

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000792834	SCV000932156	benign	Amyotrophic lateral sclerosis type 4; Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	2023-11-22	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV001644824	SCV001145565	likely benign	not specified	2021-01-08	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001169647	SCV001332401	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.
Illumina Laboratory Services, Illumina	RCV001169648	SCV001332402	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.
GeneDx	RCV000992948	SCV001773503	uncertain significance	not provided	2022-12-15	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified as a single heterozygous variant in an individual with spastic paraplegia, but familial segregation information and additional clinical information were not included (D'Amore et al., 2018); This variant is associated with the following publications: (PMID: 30564185)
Ambry Genetics	RCV002352314	SCV002661290	uncertain significance	Inborn genetic diseases	2022-01-27	criteria provided, single submitter	clinical testing	The p.I2041T variant (also known as c.6122T>C), located in coding exon 14 of the SETX gene, results from a T to C substitution at nucleotide position 6122. The isoleucine at codon 2041 is replaced by threonine, an amino acid with similar properties. This alteration was detected in an individual with a confirmed diagnosis of hereditary spastic paraplegia; however, clinical details were limited (D'Amore A et al. Front Neurol, 2018 Dec;9:981). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000992948	SCV001553233	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004538088	SCV004709565	uncertain significance	SETX-related disorder	2024-09-06	no assertion criteria provided	clinical testing	The SETX c.6122T>C variant is predicted to result in the amino acid substitution p.Ile2041Thr. This variant was reported in an individual with spastic paraplegia (D'Amore et al. 2018. PubMed ID: 30564185). This variant is reported in 0.18% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.