Submissions for variant NM_015046.7(SETX):c.7330C>T (p.Arg2444Cys)

gnomAD frequency: 0.00002  dbSNP: rs372535542

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000778875	SCV000915273	uncertain significance	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	2017-10-12	criteria provided, single submitter	clinical testing	The SETX c.7330C>T (p.Arg2444Cys) missense variant has been reported in a compound heterozygous state with two variants on the second allele in a 35 year old male with ataxia with oculomotor apraxia type 2 (Bernard et al. 2008). This individual presented at age 12, required the use of a wheelchair by age 34, and had limb ataxia, cerebellar dysarthria, oculomotor apraxia and neuropathy with muscular atrophy and areflexia. The p.Arg2444Cys variant was also detected in a heterozygous state in the patient's presumably healthy father. The variant was absent from 100 control subjects but reported at a frequency of 0.000012 in the Total population from the Genome Aggregation Database. The evidence for this variant is limited. Therefore, the p.Arg2444Cys variant is classified as a variant of unknown significance but suspicious for pathogenicity for ataxia with oculomotor apraxia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Illumina Laboratory Services, Illumina	RCV001169582	SCV001332321	uncertain significance	Amyotrophic lateral sclerosis type 4	2017-10-09	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.
MGZ Medical Genetics Center	RCV000778875	SCV002580030	likely pathogenic	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	2021-11-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002386359	SCV002669788	uncertain significance	Inborn genetic diseases	2022-03-25	criteria provided, single submitter	clinical testing	The p.R2444C variant (also known as c.7330C>T), located in coding exon 24 of the SETX gene, results from a C to T substitution at nucleotide position 7330. The arginine at codon 2444 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was detected in an individual with cerebellar dysarthria, oculomotor apraxia, neuropathy with muscular atrophy and areflexia, and increased serum AFP, who also two other SETX variants on a different alelle (Bernard V et al. Neuropediatrics, 2008 Dec;39:347-50). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.