ClinVar Miner

Submissions for variant NM_001008212.2(OPTN):c.1442C>T (p.Ala481Val)

gnomAD frequency: 0.00004  dbSNP: rs377219791
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV000516745 SCV000614400 uncertain significance not specified 2016-12-29 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001106773 SCV001263869 uncertain significance Amyotrophic lateral sclerosis type 12 2017-04-27 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.
Illumina Laboratory Services, Illumina RCV001106774 SCV001263870 uncertain significance Primary open angle glaucoma 2017-04-27 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV001359911 SCV001555800 uncertain significance Primary open angle glaucoma; Amyotrophic lateral sclerosis type 12; Glaucoma 1, open angle, E 2024-12-30 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 481 of the OPTN protein (p.Ala481Val). This variant is present in population databases (rs377219791, gnomAD 0.006%). This missense change has been observed in individual(s) with autosomal dominant and recessive amyotrophic lateral sclerosis (PMID: 21074290, 25943890, 32028661). ClinVar contains an entry for this variant (Variation ID: 447910). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt OPTN protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV002525058 SCV003528141 uncertain significance Inborn genetic diseases 2022-12-08 criteria provided, single submitter clinical testing Unlikely to be causative of OPTN-related amyotrophic lateral sclerosis (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences RCV004735588 SCV005350576 uncertain significance OPTN-related disorder 2024-03-14 no assertion criteria provided clinical testing The OPTN c.1442C>T variant is predicted to result in the amino acid substitution p.Ala481Val. This variant has been reported in individuals with amyotrophic lateral sclerosis (Belzil et al. 2011. PubMed ID: 21074290; Pensato et al. 2020. PubMed ID: 32028661). This variant was also reported in the compound heterozygous state in an individual with frontotemporal lobar degeneration (Pottier et al. 2015. PubMed ID: 25943890). This variant is reported in 0.0056% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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