Submissions for variant NM_015046.7(SETX):c.2479A>G (p.Lys827Glu)

gnomAD frequency: 0.00058  dbSNP: rs150532677

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000540061	SCV000645241	likely benign	Amyotrophic lateral sclerosis type 4; Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	2024-01-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000762582	SCV000892915	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	SETX: BS1
Athena Diagnostics	RCV001000648	SCV001145538	likely benign	not specified	2020-10-22	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000648	SCV001157672	uncertain significance	not specified	2018-10-02	criteria provided, single submitter	clinical testing	The SETX c.2479A>G; p.Lys827Glu variant (rs150532677), is reported in at least one family affected with autosomal dominant tremor and ataxia (Vasco 2017). This variant is reported as uncertain significance in ClinVar (Variation ID: 468494), and is found in the general population with an overall allele frequency of 0.078% (212/272,300 alleles) in the Genome Aggregation Database. The lysine at codon 827 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Lys827Glu variant is uncertain at this time. References: Vasco G, et al. Novel mutation in SETX causes a dominant pleiotropic Tremor-Ataxia phenotype across three generations (abstract) In: International Ataxia Research Conference; 2017 Sept 27-30; Pisa, Italy. Genova, Italy: Eurotraining; 2017. Abstract nr 66.
Illumina Laboratory Services, Illumina	RCV001167461	SCV001329964	uncertain significance	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001167462	SCV001329965	uncertain significance	Amyotrophic lateral sclerosis type 4	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001167461	SCV001369766	uncertain significance	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	2018-10-11	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: BS1.
GeneDx	RCV000762582	SCV001766568	likely benign	not provided	2021-05-13	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001848950	SCV002105137	uncertain significance	Hereditary spastic paraplegia	2020-05-01	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252164	SCV002523505	likely benign	See cases	2020-02-10	criteria provided, single submitter	clinical testing	ACMG classification criteria: BS1, BP4
Ambry Genetics	RCV002456164	SCV002737495	uncertain significance	Inborn genetic diseases	2022-01-06	criteria provided, single submitter	clinical testing	The p.K827E variant (also known as c.2479A>G), located in coding exon 8 of the SETX gene, results from an A to G substitution at nucleotide position 2479. The lysine at codon 827 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is well 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 juvenile amyotrophic lateral sclerosis 4 (ALS4); however, its contribution to the development of spinocerebellar ataxia with axonal neuropathy 2 (SCAN2) is uncertain.
Mayo Clinic Laboratories, Mayo Clinic	RCV000762582	SCV004225123	uncertain significance	not provided	2023-05-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001000648	SCV005185516	likely benign	not specified	2024-05-29	criteria provided, single submitter	clinical testing	Variant summary: SETX c.2479A>G (p.Lys827Glu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00084 in 246404 control chromosomes, predominantly at a frequency of 0.0014 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in SETX causing Amyotrophic Lateral Sclerosis Type 4 phenotype. To our knowledge, no occurrence of c.2479A>G in individuals affected with Amyotrophic Lateral Sclerosis Type 4 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 468494). Based on the evidence outlined above, the variant was classified as likely benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000762582	SCV001809115	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000762582	SCV001973292	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004538008	SCV004718568	likely benign	SETX-related disorder	2022-12-07	no assertion criteria provided	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).