ClinVar Miner

Submissions for variant NM_001008212.2(OPTN):c.404A>C (p.Glu135Ala)

dbSNP: rs372714385
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001934233 SCV002210026 uncertain significance Primary open angle glaucoma; Amyotrophic lateral sclerosis type 12; Glaucoma 1, open angle, E 2024-10-06 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 135 of the OPTN protein (p.Glu135Ala). This variant is present in population databases (rs372714385, gnomAD 0.06%). 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: 1438247). 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 not expected to disrupt OPTN protein function with a negative 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 RCV002324372 SCV002630145 uncertain significance Inborn genetic diseases 2021-05-28 criteria provided, single submitter clinical testing The p.E135A variant (also known as c.404A>C), located in coding exon 3 of the OPTN gene, results from an A to C substitution at nucleotide position 404. The glutamic acid at codon 135 is replaced by alanine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the supporting evidence, this variant is unlikely to be causative of autosomal dominant amyotrophic lateral sclerosis (ALS); however, its contribution to the development of autosomal recessive ALS is uncertain.
PreventionGenetics, part of Exact Sciences RCV004538658 SCV004121159 uncertain significance OPTN-related disorder 2023-05-17 criteria provided, single submitter clinical testing The OPTN c.404A>C variant is predicted to result in the amino acid substitution p.Glu135Ala. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.059% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-13154487-A-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Mayo Clinic Laboratories, Mayo Clinic RCV004793636 SCV005410936 uncertain significance not provided 2024-02-27 criteria provided, single submitter clinical testing BP4

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