ClinVar Miner

Submissions for variant NM_015046.7(SETX):c.4225A>T (p.Asn1409Tyr)

gnomAD frequency: 0.00005  dbSNP: rs373375060
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mendelics RCV000988270 SCV001137925 benign Amyotrophic lateral sclerosis type 4 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001002069 SCV001159904 uncertain significance not specified 2018-09-16 criteria provided, single submitter clinical testing The SETX: p.Asn1409Tyr variant (rs373375060) was reported in one patient with axonal CMT with disease progression including slowing of motor and sensory nerve conduction velocities (Drew 2014). This variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.004 percent (identified on 10 out of 277,124 chromosomes) and has been reported to the ClinVar database (Variation ID: 155745). The asparagine at position 1409 is weakly conserved and computational analyses of the effects of the p.Asn1409Tyr variant on protein structure and function provide conflicting results (SIFT: damaging, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Asn1409Tyr variant with certainty.
Labcorp Genetics (formerly Invitae), Labcorp RCV001041860 SCV001205506 benign Amyotrophic lateral sclerosis type 4; Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 2023-12-04 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001167322 SCV001329802 uncertain significance Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 2017-04-28 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina RCV000988270 SCV001329803 uncertain significance Amyotrophic lateral sclerosis type 4 2017-04-28 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.
Ambry Genetics RCV002326848 SCV002630760 uncertain significance Inborn genetic diseases 2021-09-17 criteria provided, single submitter clinical testing The p.N1409Y variant (also known as c.4225A>T), located in coding exon 8 of the SETX gene, results from an A to T substitution at nucleotide position 4225. The asparagine at codon 1409 is replaced by tyrosine, an amino acid with dissimilar properties. This variant was detected in an individual with Charcot-Marie-Tooth disease type 2 as well as her possibly affected child; however, clinical details were limited (Drew AP et al. Mol Genet Genomic Med, 2015 Mar;3:143-54). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences RCV004532621 SCV004109527 uncertain significance SETX-related disorder 2023-03-08 criteria provided, single submitter clinical testing The SETX c.4225A>T variant is predicted to result in the amino acid substitution p.Asn1409Tyr. This variant was reported in an individual with a Charcot-Marie-Tooth type 2 disease phenotype (Family L, Table 3, Drew et al 2015. PubMed ID: 25802885). This variant is reported in 0.0085% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-135202760-T-A). This variant is interpreted as no interpretation set. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Athena Diagnostics RCV000143816 SCV004230037 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 uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Computational tools disagree on the variant's effect on normal protein function.
Northcott Neuroscience Laboratory, ANZAC Research Institute RCV000143816 SCV000188709 probable-non-pathogenic not provided no assertion criteria provided not provided Converted during submission to Likely benign.
Inherited Neuropathy Consortium RCV000790204 SCV000929596 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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