Submissions for variant NM_130837.3(OPA1):c.2873_2876del

dbSNP: rs80356530

Total submissions: 32

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000081763	SCV000228466	pathogenic	not provided	2017-01-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000081763	SCV000252013	pathogenic	not provided	2020-02-24	criteria provided, single submitter	clinical testing	An Opa1 mouse model carrying the c.2708_2711delTTAG variant displayed a multi-systemic poly-degenerative phenotype including signs of visual failure, deafness, encephalomyopathy, peripheral neuropathy, ataxia, cardiomyopathy, and premature age-related axonal and myelin degenerations (Sarzi et al., 2012); Frameshift 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; This variant is associated with the following publications: (PMID: 23665194, 25012220, 26031781, 21646330, 25699009, 26385429, 27260406, 25564500, 23250881, 27974645, 11017079, 28848318, 15505825, 20952381, 11440989, 32025183, 31500643, 31589614, 33300680)
Athena Diagnostics	RCV000081763	SCV000614384	pathogenic	not provided	2022-12-07	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. This variant is one of the most common pathogenic variants associated with autosomal dominant optic atrophy (ADOA; PMID: 11440989, 22857269), and therefore the frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been reported to exhibit reduced penetrance (PMID: 11440989). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 18222991) This variant occurs with an alternate explanation for disease significantly less often than expected, suggesting this variant may be associated with disease.
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000005387	SCV000693465	pathogenic	Autosomal dominant optic atrophy classic form	2017-09-18	criteria provided, single submitter	clinical testing	This frameshift variant (deletion of four nucleotides) in the OPA1 gene was identified in a male young patient and also his mother, both diagnosed with optic atrophy 1.
Blueprint Genetics	RCV001073751	SCV001239311	pathogenic	Retinal dystrophy	2017-10-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000081763	SCV001246487	pathogenic	not provided	2021-07-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000081763	SCV001446520	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	RCV000005387	SCV001519161	pathogenic	Autosomal dominant optic atrophy classic form	2021-01-04	criteria provided, single submitter	research
Institute of Medical Molecular Genetics, University of Zurich	RCV000005387	SCV001548160	likely pathogenic	Autosomal dominant optic atrophy classic form	2021-01-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000081763	SCV001591733	pathogenic	not provided	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val903Glyfs*3) 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 present in population databases (rs745560444, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with dominant optic atrophy (PMID: 11017079, 26385429). It has also been observed to segregate with disease in related individuals. This variant is also known as c.2708delTTAG and c.2873_2876delTTAG (p.V958Gfs*3). ClinVar contains an entry for this variant (Variation ID: 5082). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Genomics England Pilot Project, Genomics England	RCV001542739	SCV001760119	likely pathogenic	Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy		criteria provided, single submitter	clinical testing
3billion	RCV000005387	SCV002318897	pathogenic	Autosomal dominant optic atrophy classic form	2022-03-22	criteria provided, single submitter	clinical testing	Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 20417570, 14961560). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Institute of Human Genetics, University Hospital Muenster	RCV004584316	SCV002577870	pathogenic	See cases	2023-03-06	criteria provided, single submitter	clinical testing	ACMG categories: PVS1,PP1,PP4,PP5
MGZ Medical Genetics Center	RCV000005387	SCV002579707	pathogenic	Autosomal dominant optic atrophy classic form	2021-11-26	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490322	SCV002777553	pathogenic	Abortive cerebellar ataxia; Glaucoma, normal tension, susceptibility to; Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy; Autosomal dominant optic atrophy classic form; Mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type)	2021-07-22	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000081763	SCV002818199	pathogenic	not provided	2022-12-17	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000081763	SCV003824243	pathogenic	not provided	2022-01-12	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000005387	SCV004032248	pathogenic	Autosomal dominant optic atrophy classic form	2023-06-20	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS4,PS3_MOD
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000005387	SCV004045808	pathogenic	Autosomal dominant optic atrophy classic form	2023-08-17	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532291	SCV004120905	pathogenic	OPA1-related disorder	2023-08-31	criteria provided, single submitter	clinical testing	The OPA1 c.2873_2876delTTAG variant is predicted to result in a frameshift and premature protein termination (p.Val958Glyfs*3). This variant is also often denoted as c.2708_2711delTTAG (p.Val903Glyfs*3) in the alternate transcript NM_015560.2. This variant has been reported many times as causative for autosomal dominant optic atrophy (see for examples Delettre et al. 2000. PubMed ID: 11017079; Pretegiani et al. 2011. PubMed ID: 21646330; Gaier et al. 2017. PubMed ID: 28848318; Lin et al. 2021. PubMed ID: 34573359). This variant has also been reported in the compound heterozygous state in an individual with early-onset Behr syndrome and the unaffected mother was a carrier of this variant, suggesting there may be incomplete penetrance (Bonneau et al. 2014. PubMed ID: 25012220). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-193384956-CAGTT-C). Frameshift variants in OPA1 are expected to be pathogenic, and this variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/5082). Given all the evidence, we interpret c.2873_2876del (p.Val958Glyfs*3) as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000081763	SCV004226069	pathogenic	not provided	2022-10-21	criteria provided, single submitter	clinical testing	PP1, PS4, PVS1
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004532291	SCV005061372	pathogenic	OPA1-related disorder	2024-03-18	criteria provided, single submitter	clinical testing	Variant summary: OPA1 c.2708_2711delTTAG (p.Val903GlyfsX3) 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. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 3' acceptor site. Three predict the variant creates a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.2e-05 in 251242 control chromosomes (gnomAD). c.2708_2711delTTAG has been reported in the literature in multiple individuals affected with autosomal dominant optic atrophy (Cohn_2008). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and this variant showed it was more prone to cell death than controls after an exogenous oxidative stress in fibroblasts (Zanna_2008). The following publications have been ascertained in the context of this evaluation (PMID: 17306754, 18222991). ClinVar contains an entry for this variant (Variation ID: 5082). Based on the evidence outlined above, the variant was classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000005387	SCV005398583	pathogenic	Autosomal dominant optic atrophy classic form	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with OPA1-related conditions (OMIM). (I) 0108 - This gene is associated with both recessive and dominant disease. Truncating variants and mutations in the C-terminal domain are associated with dominant optic atrophy. Individuals carrying missense variants clustered within the GTPase domain generally develop optic atrophy plus syndrome. Lastly, biallelic variants have been associated with early-onset Behr syndrome (PMIDs: 31500643, 28494813, 25012220, 30165240). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 17306754). In addition, this variant has been specifically reported to have a penetrance ranging from 43-62% (PMID: 11440989). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2 and v3) <0.01 (15 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic or pathogenic by multiple clinical diagnostic laboratories (ClinVar) and is regarded as a pathogenic variant in GeneReviews. While this variant has primarily been reported in individuals with autosomal dominant optic atropy, it has also been reported as compound heterozygous in two siblings with Behr syndrome. The father of the siblings, who is heterozygous for the variant, was diagnosed with mild optic atrophy and bilateral sensorineural hearing loss (PMID: 21636302, OMIM). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Skin fibroblasts from affected individuals heterozygous for this variant demonstrated reduced OPA1 protein levels and abnormal mitochondrial morphology and fusion compared to control fibroblasts (PMID: 18222991). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000005387	SCV000025567	pathogenic	Autosomal dominant optic atrophy classic form	2011-08-01	no assertion criteria provided	literature only
GeneReviews	RCV000005387	SCV000041284	not provided	Autosomal dominant optic atrophy classic form		no assertion provided	literature only
OMIM	RCV000210745	SCV000266834	pathogenic	Abortive cerebellar ataxia	2011-08-01	no assertion criteria provided	literature only
Wellcome Centre for Mitochondrial Research, Newcastle University	RCV000508703	SCV000575923	pathogenic	Mitochondrial disease	2017-04-07	no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV000005387	SCV000606947	not provided	Autosomal dominant optic atrophy classic form		no assertion provided	phenotyping only	Variant was identified in multiple participants. Variant interpreted as Pathogenic and reported, most recently, on 11-07-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Clinical Genetics, Academic Medical Center	RCV000081763	SCV001921462	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000081763	SCV001974149	pathogenic	not provided		no assertion criteria provided	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000005387	SCV001984459	pathogenic	Autosomal dominant optic atrophy classic form	2020-10-18	flagged submission	clinical testing
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV003319160	SCV004023198	likely pathogenic	Tip-toe gait	2022-11-23	flagged submission	clinical testing	Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed.