Submissions for variant NM_001008212.2(OPTN):c.703C>T (p.Gln235Ter)

gnomAD frequency: 0.00001  dbSNP: rs1371904281

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002871820	SCV003235598	pathogenic	Primary open angle glaucoma; Amyotrophic lateral sclerosis type 12; Glaucoma 1, open angle, E	2024-06-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln235*) 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). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with OPTN-related conditions (PMID: 25382069, 25943890, 30739198). ClinVar contains an entry for this variant (Variation ID: 2030520). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002898610	SCV003536175	uncertain significance	Inborn genetic diseases	2020-04-30	criteria provided, single submitter	clinical testing	The c.703C>T (p.Q235*) alteration, located in exon 6 (coding exon 5) of the OPTN gene, consists of a C to T substitution at nucleotide position 703. This changes the amino acid from a glutamine (Q) to a stop codon at amino acid position 235. Premature stop codons are typically deleterious in nature (Richards, 2015). The alteration change is ultra rare in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the OPTN c.703C>T alteration was observed in <0.001% (1/251,484) total alleles studied. The amino acid change has been observed in affected individuals: _x000D_ _x000D_ The p.Q235* alteration was detected once among 391 individuals with amyotrophic lateral sclerosis (ALS) in a pooled-sample sequencing of 17 genes associated with ALS. Specifically, the alteration was detected in 1/698 sporadic ALS alelles and 0/84 familial ALS alleles (Cady, 2015). Additionally, this alteration was reported in a patient with frontotemporal dementia, who also had a second missene alteration in OPTN (p.A481V), which studies suggest was located in trans to the p.Q235* alteration (Pottier, 2015). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV004719275	SCV005325398	likely pathogenic	not provided	2023-05-22	criteria provided, single submitter	clinical testing	Observed in a patient with frontotemporal lobar degeneration (FTLD) who harbored an additional OPTN variant in trans (Pottier et al., 2015); Reported in an individual with sporadic limb onset amyotrophic lateral sclerosis (Cady et al., 2015); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25943890, 29080331, 28456633, 32028661, 29605155, 31498468, 30739198, 25382069, 32687832)
PreventionGenetics, part of Exact Sciences	RCV004736215	SCV005363997	pathogenic	OPTN-related disorder	2024-02-19	no assertion criteria provided	clinical testing	The OPTN c.703C>T variant is predicted to result in premature protein termination (p.Gln235*). This variant has been reported in an individual with amyotrophic lateral sclerosis (ALS, Table S1, Cady et al. 2015. PubMed ID: 25382069). This variant has also been reported in the compound heterozygous state in an individual with a pathological diagnosis of frontotemporal lobar dementia (Case A, Pottier et al. 2015. PubMed ID: 25943890). Post-mortem pathology demonstrated p62 and TDP-43 pathology in the cortical gray matter and quantitative mRNA expression from brain tissue demonstrated OPTN mRNA and protein expression were dramatically reduced in this patient (Figures 4 and 2, respectively, Pottier et al. 2015. PubMed ID: 25943890). This variant is reported in 0.00088% of alleles in individuals of European (non-Finnish) descent in gnomAD. Nonsense variants in OPTN are expected to be pathogenic and several nonsense variants upstream and downstream of this variant have been reported in individuals with ALS (Human Gene Mutation Database). This variant is interpreted as pathogenic.