Submissions for variant NM_130837.3(OPA1):c.2296C>T (p.Arg766Ter)

dbSNP: rs863224906

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
UCLA Clinical Genomics Center, UCLA	RCV000199194	SCV000255432	likely pathogenic	Autosomal dominant optic atrophy classic form	2012-10-30	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756450	SCV000884269	pathogenic	not provided	2018-05-18	criteria provided, single submitter	clinical testing	The OPA1 c.2296C>T; p.Arg766Ter variant (rs863224906; ClinVar Variation ID: 216979) has been previously identified in an individual with a personal and family consistent with dominantly inherited optic atrophy (Delettre 2001). Located in exon 23 (of 31) is variant is expected to result in a truncated or absent protein product. Additionally, this variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database). As loss of function is an established disease mechanism in OPA1-mediated optic atrophy, based on the available information, this variant is considered pathogenic. Pathogenic variants in OPA1 are associated with autosomal dominant optic atrophy 1 (MIM: 165500) and autosomal recessive Behr syndrome (MIM: 210000).
CeGaT Center for Human Genetics Tuebingen	RCV000756450	SCV001246484	pathogenic	not provided	2017-12-01	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000756450	SCV001880549	pathogenic	not provided	2021-05-11	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with dominant optic atrophy (DOA).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000756450	SCV002239003	pathogenic	not provided	2024-05-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg711*) in the OPA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OPA1 are known to be pathogenic (PMID: 11440988, 20157015, 20952381, 25012220). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with optic atrophy (PMID: 11810270). ClinVar contains an entry for this variant (Variation ID: 216979). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000756450	SCV003845600	pathogenic	not provided	2023-01-03	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22865259, 25525159, 33841295, 11810270, 34242285)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987447	SCV004804334	pathogenic	OPA1-related disorder	2024-01-09	criteria provided, single submitter	clinical testing	Variant summary: OPA1 c.2131C>T (p.Arg711X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251228 control chromosomes (gnomAD). c.2131C>T has been reported in the literature in individuals affected with OPA1-Related Disorders (examples: Delettre_2001, Reis_2013, Li_2017). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11810270, 28081242, 22865259). ClinVar contains an entry for this variant (Variation ID: 216979). Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003987447	SCV004800372	pathogenic	OPA1-related disorder	2024-03-19	no assertion criteria provided	clinical testing	The OPA1 c.2296C>T variant is predicted to result in premature protein termination (p.Arg766*). This variant can also be denoted as c.2131C>T (p.Arg711*) in the transcript NM_015560. This variant has been reported in individuals with autosomal dominant optic atrophy (see for examples Delettre et al. 2001. PubMed ID: 11810270; Weisschuh et al. 2021. PubMed ID: 34242285). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in OPA1 are expected to be pathogenic. Given the evidence, we interpret this variant as pathogenic.
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004816340	SCV005073614	pathogenic	Optic atrophy	2020-01-01	no assertion criteria provided	clinical testing