Submissions for variant NM_001008212.2(OPTN):c.403G>T (p.Glu135Ter)

dbSNP: rs140599944

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000778274	SCV000914448	uncertain significance	Amyotrophic lateral sclerosis type 12	2018-12-18	criteria provided, single submitter	clinical testing	The OPTN c.403G>T (p.Glu135Ter) variant is a stop-gained variant predicted to result in premature termination of the protein product. The p.Glu135Ter variant has been reported in one study in which it is found in a homozygous state in one patient with amyotrophic lateral sclerosis (Müller et al. 2018). Control data are unavailable for this variant, which is reported at a frequency of 0.000081 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the potential impact of stop-gained variants and the limited evidence from the literature, the p.Glu135Ter variant is classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive amyotrophic lateral sclerosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Illumina Laboratory Services, Illumina	RCV001105536	SCV001262507	benign	Primary open angle glaucoma	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Invitae	RCV001869132	SCV002214900	pathogenic	Primary open angle glaucoma; Amyotrophic lateral sclerosis type 12; Glaucoma 1, open angle, E	2022-10-24	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 631627). This premature translational stop signal has been observed in individual(s) with autosomal recessive amyotrophic lateral sclerosis (PMID: 29650794). This variant is present in population databases (rs140599944, gnomAD 0.008%). This sequence change creates a premature translational stop signal (p.Glu135*) in the OPTN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OPTN are known to be pathogenic (PMID: 20428114).
Laboratory for Molecular Genetic Diagnostic of Neurological Diseases, University of Belgrade, School of Medicine	RCV000778274	SCV001805843	pathogenic	Amyotrophic lateral sclerosis type 12	2021-03-01	no assertion criteria provided	clinical testing