Submissions for variant NM_015046.7(SETX):c.4096T>C (p.Ser1366Pro)

gnomAD frequency: 0.00030  dbSNP: rs140147684

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000549234	SCV000645256	likely benign	Amyotrophic lateral sclerosis type 4; Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	2025-01-20	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001167927	SCV001330474	likely benign	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001167928	SCV001330475	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.
Athena Diagnostics	RCV001288399	SCV001475479	likely benign	not provided	2020-01-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001288399	SCV001502109	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	SETX: BP4
Mayo Clinic Laboratories, Mayo Clinic	RCV001288399	SCV001716043	uncertain significance	not provided	2019-04-07	criteria provided, single submitter	clinical testing
GeneDx	RCV001288399	SCV002559449	likely benign	not provided	2022-04-12	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function
Ambry Genetics	RCV002323994	SCV002630568	uncertain significance	Inborn genetic diseases	2022-04-25	criteria provided, single submitter	clinical testing	The p.S1366P variant (also known as c.4096T>C), located in coding exon 8 of the SETX gene, results from a T to C substitution at nucleotide position 4096. The serine at codon 1366 is replaced by proline, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the supporting evidence, this variant is unlikely to be causative of autosomal dominant juvenile amyotrophic lateral sclerosis 4 (ALS4); however, its contribution to the development of autosomal recessive spinocerebellar ataxia with axonal neuropathy 2 (SCAN2) is uncertain.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782439	SCV005394488	uncertain significance	not specified	2024-09-13	criteria provided, single submitter	clinical testing	Variant summary: SETX c.4096T>C (p.Ser1366Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00025 in 251310 control chromosomes in the gnomAD database, including 1 homozygote. c.4096T>C has been reported in the literature in individuals affected with congenital hypotonia or distal hereditary motor neuropathy. Co-occurrences with other pathogenic variants were reported in these probands (IGHMBP2 c.1488C>A, p.Cys496Ter and c.1346delT, p.Met449Serfs*24 in one case; HSPB1 c.379C>T, p.Arg127Trp in the other case). These reports do not provide unequivocal conclusions about association of the variant with Amyotrophic Lateral Sclerosis Type 4. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26257172, 36539320). ClinVar contains an entry for this variant (Variation ID: 468505). Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001288399	SCV001809268	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001288399	SCV001922851	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004541717	SCV004775377	likely benign	SETX-related disorder	2022-07-31	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).