Submissions for variant NM_015046.7(SETX):c.4433C>A (p.Ala1478Glu)

gnomAD frequency: 0.00034  dbSNP: rs143661911

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV001644615	SCV000615189	benign	not specified	2020-11-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000550269	SCV000645259	likely benign	Amyotrophic lateral sclerosis type 4; Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	2023-12-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000550269	SCV000895959	uncertain significance	Amyotrophic lateral sclerosis type 4; Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001165737	SCV001327968	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). 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	RCV001167321	SCV001329801	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). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000518326	SCV001716041	uncertain significance	not provided	2019-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000518326	SCV001817190	uncertain significance	not provided	2024-11-20	criteria provided, single submitter	clinical testing	Reported previously in an individual with corticobasal syndrome who had a loss of function variant in another gene associated with this disorder, and the authors concluded that the SETX variant was unlikely to be the cause the disorder (PMID: 35309588); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28642336, 32409511, 35309588, 23129421)
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001848902	SCV002105158	uncertain significance	Hereditary spastic paraplegia	2019-07-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002329225	SCV002628306	uncertain significance	Inborn genetic diseases	2023-10-13	criteria provided, single submitter	clinical testing	The c.4433C>A (p.A1478E) alteration is located in exon 10 (coding exon 8) of the SETX gene. This alteration results from a C to A substitution at nucleotide position 4433, causing the alanine (A) at amino acid position 1478 to be replaced by a glutamic acid (E). Based on data from gnomAD, the A allele has an overall frequency of 0.028% (78/282780) total alleles studied. The highest observed frequency was 0.055% (4/7224) of Other alleles. This alteration was reported in a female with symmetrical lower limb amyotrophic paraparesis, onset in middle age. The alteration was absent in two healthy family members and was present in sample from her deceased father, who had generalized muscular atrophy; it was also present in one unrelated unaffected German control included in the study and in 2 control individuals in a different study of individuals with sporadic amyotrophic lateral sclerosis (Arning, 2013; Gibson, 2017). Additionally, this variant was reported in one Australian individual of German ancestry with clinical features suggesting amyotrophic lateral sclerosis (ALS); however, this variant has also been reported in one individual with corticobasal syndrome who has a variant in TBK1, a gene central to the development of ALS (McCann, 2020; Seibert, 2022). This amino acid position is not well conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV000518326	SCV004156608	uncertain significance	not provided	2023-09-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537862	SCV004116619	uncertain significance	SETX-related disorder	2024-05-24	no assertion criteria provided	clinical testing	The SETX c.4433C>A variant is predicted to result in the amino acid substitution p.Ala1478Glu. This variant was reported in individuals with amyotrophic lateral sclerosis (Arning et al. 2013. PubMed ID: 23129421; McCann et al. 2020. PubMed ID: 32409511) as well as in unaffected controls (Arning et al. 2013. PubMed ID: 23129421). This variant is reported in 0.052% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which may be too common to be a primary cause of disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.