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

gnomAD frequency: 0.00004  dbSNP: rs377219791

Total submissions: 6

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.