ClinVar Miner

Submissions for variant NM_001008212.2(OPTN):c.785C>A (p.Ser262Ter)

gnomAD frequency: 0.00001  dbSNP: rs750571210
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001958587 SCV002229327 pathogenic Primary open angle glaucoma; Amyotrophic lateral sclerosis type 12; Glaucoma 1, open angle, E 2024-08-31 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser262*) 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 (rs750571210, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with autosomal recessive amyotrophic lateral sclerosis and frontotemporal dementia (PMID: 29558868). ClinVar contains an entry for this variant (Variation ID: 1455344). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV002407182 SCV002670936 pathogenic Inborn genetic diseases 2021-01-06 criteria provided, single submitter clinical testing The p.S262* variant (also known as c.785C>A), located in coding exon 6 of the OPTN gene, results from a C to A substitution at nucleotide position 785. This changes the amino acid from a serine to a stop codon within coding exon 6. This alteration has been reported in trans with another OPTN variant in a patient with amyotrophic lateral sclerosis and frontotemporal dementia (Pottier C et al. Amyotroph Lateral Scler Frontotemporal Degene, 2018 08;19:469-471). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation for autosomal recessive amyotrophic lateral sclerosis (ALS). Although biallelic loss of function alterations in OPTN have been associated with autosomal recessive ALS, haploinsufficiency for OPTN has not been clearly established as a mechanism of disease for autosomal dominant ALS. Since supporting evidence is limited at this time, the clinical significance of this alteration for autosomal dominant ALS remains unclear.

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