ClinVar Miner

Submissions for variant NM_015046.7(SETX):c.472T>G (p.Leu158Val) (rs145438764)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000350037 SCV000477889 likely benign Ataxia with Oculomotor Apraxia 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000399144 SCV000477890 benign 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx RCV000480824 SCV000565556 uncertain significance not specified 2016-04-01 criteria provided, single submitter clinical testing The L158V variant in the SETX gene has been reported in an individual with Parkinson disease and second individual from a cohort of individuals with amyotrophic lateral sclerosis; however the further evidence to support the pathogenicity of this alteration was not provided in either report (Ghani et al., 2015; Cady et al., 2015). In addition, the NHLBI ESP Exome Sequencing Project reports L158V was observed in 47/8600 alleles (0.55%) from individuals of European American background; no individuals within this control group were reported as homozygous for this variant. The L158V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, we interpret L158V as a variant of uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000480824 SCV000605100 uncertain significance not specified 2018-10-15 criteria provided, single submitter clinical testing The SETX c.472T>G; p.Leu158Val variant (rs145438764) is reported in the literature in individuals affected with amyotrophic lateral sclerosis (Cady 2015, Lamp2018) or Parkinson's disease (Ghani 2015), although none of these studies concluded whether this variant is pathogenic for either of those diseases. This variant is reported as uncertain significance or likely benign in ClinVar (Variation ID: 365376), and is found in the general population with an overall allele frequency of 0.37% (1040/282,792 alleles) in the Genome Aggregation Database. The leucine at codon 158 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of the p.Leu158Val variant is uncertain at this time. Pathogenic variants in the SETX gene have been associated with autosomal dominant juvenile amyotrophic lateral sclerosis 4 (ALS4) (MIM: 602433) and autosomal recessive spinocerebellar ataxia 1 (MIM: 606002), both of which can present with symptoms similar to Charcot Marie Tooth disease. Based on population frequency, this variant is unlikely to be causative for ALS4. However, a role in spinocerebellar ataxia 1 cannot be ruled out. References: Cady et al. Amyotrophic lateral sclerosis onset is influenced by the burden of rare variants in known amyotrophic lateral sclerosis genes. Ann Neurol. 2015; 77(1): 100-113. Ghani et al. Mutation analysis of patients with neurodegenerative disorders using NeuroX array. Neurobiol Aging. 2015; 36(1): 545. e9-14. Lamp M et al. Twenty years of molecular analyses in amyotrophic lateral sclerosis: genetic landscape of Italian patients. Neurobiol Aging. 2018 Jun;66:179.e5-179.e16.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000513524 SCV000609358 uncertain significance not provided 2019-07-01 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000513524 SCV000615191 benign not provided 2018-11-30 criteria provided, single submitter clinical testing
Invitae RCV001080659 SCV000645266 likely benign Amyotrophic lateral sclerosis type 4; Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 2019-12-31 criteria provided, single submitter clinical testing

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