Submissions for variant NM_001008212.2(OPTN):c.127C>T (p.Gln43Ter)

gnomAD frequency: 0.00006  dbSNP: rs934287314

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000578674	SCV000681111	likely pathogenic	not provided	2017-11-15	criteria provided, single submitter	clinical testing	The Q43X variant in the OPTN gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Q43X variant is observed in 2/15000 (0.013%) alleles from individuals of non-Finnish European background in the ExAC dataset (Lek et al., 2016). We interpret Q43X as a likely pathogenic variant.
Illumina Laboratory Services, Illumina	RCV000778273	SCV000914447	uncertain significance	OPTN-Related Disorders	2018-10-29	criteria provided, single submitter	clinical testing	The OPTN c.127C>T (p.Gln43Ter) variant is a stop gained variant that is predicted to result in an absent or prematurely truncated protein. A literature search was performed for the gene, cDNA change, and protein consequence. No publications were found through this search. The p.Gln43Ter variant occurs in a region of good sequencing coverage and is reported in one allele of the Latino population of the Exome Aggregation Consortium; however, the variant occurs in phase with a second variant that alters its functional interpretation. Based on the potential impact of stop-gained variants and the lack of clarifying evidence, the p.Gln43Ter variant is classified as a variant of unknown significance but suspicious for pathogenicity for OPTN-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV001860012	SCV002229250	pathogenic	Primary open angle glaucoma; Amyotrophic lateral sclerosis type 12; Glaucoma 1, open angle, E	2022-06-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln43*) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with OPTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 489125). For these reasons, this variant has been classified as Pathogenic.