ClinVar Miner

Submissions for variant NM_015046.7(SETX):c.4225A>T (p.Asn1409Tyr) (rs373375060)

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Total submissions: 7
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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.
Invitae RCV001041860 SCV001205506 uncertain significance Amyotrophic lateral sclerosis type 4; Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 2019-12-10 criteria provided, single submitter clinical testing This sequence change replaces asparagine with tyrosine at codon 1409 of the SETX protein (p.Asn1409Tyr). The asparagine residue is weakly conserved and there is a large physicochemical difference between asparagine and tyrosine. This variant is present in population databases (rs373375060, ExAC 0.007%). This variant has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 25802885). ClinVar contains an entry for this variant (Variation ID: 155745). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Clinical Services Laboratory,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 Clinical Services Laboratory,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.
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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