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

gnomAD frequency: 0.00005  dbSNP: rs373375060

Total submissions: 10

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	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	RCV003415971	SCV004109527	uncertain significance	SETX-related condition	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 Inc	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