ClinVar Miner

Submissions for variant NM_001008212.2(OPTN):c.1352T>C (p.Ile451Thr)

gnomAD frequency: 0.00001  dbSNP: rs772864480
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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 RCV003058244 SCV003441608 uncertain significance Primary open angle glaucoma; Amyotrophic lateral sclerosis type 12; Glaucoma 1, open angle, E 2023-03-25 criteria provided, single submitter clinical testing 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt OPTN protein function. ClinVar contains an entry for this variant (Variation ID: 2136845). This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 26503823). This variant is present in population databases (rs772864480, gnomAD 0.003%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 451 of the OPTN protein (p.Ile451Thr).
Ambry Genetics RCV003170967 SCV003887389 uncertain significance Inborn genetic diseases 2023-01-10 criteria provided, single submitter clinical testing The c.1352T>C (p.I451T) alteration is located in exon 11 (coding exon 10) of the OPTN gene. This alteration results from a T to C substitution at nucleotide position 1352, causing the isoleucine (I) at amino acid position 451 to be replaced by a threonine (T). Based on data from gnomAD, the C allele has an overall frequency of 0.001% (2/251476) total alleles studied. The highest observed frequency was 0.0326% (2/6138) of Other alleles. This variant has been previously reported in a patient with sporadic ALS (Li, 2015). This amino acid position is well conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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