VCV000005082.65 - ClinVar

NM_130837.3(OPA1):c.2873_2876del

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(33)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_130837.3(OPA1):c.2873_2876del

Variation ID: 5082 Accession: VCV000005082.65

Type and length

Deletion, 4 bp

Location

Cytogenetic: 3q29 3: 193667168-193667171 (GRCh38) [ NCBI UCSC ] 3: 193384957-193384960 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Nov 14, 2015	Jan 25, 2025	Nov 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_130837.3:c.2873-2_2874del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NM_130837.3:c.2873_2876del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NM_015560.3:c.2708_2711delTTAG		splice acceptor
NM_130837.2:c.2873_2876del
NC_000003.12:g.193667170_193667173del
NC_000003.11:g.193384959_193384962del
NG_011605.1:g.79027_79030del
LRG_337:g.79027_79030del
LRG_337t1:c.2708_2711del
LRG_337t2:c.2873_2876del

... more HGVS ... less HGVS

Protein change

Other names

p.Val903Glyfs*3

Canonical SPDI

NC_000003.12:193667167:AGTTAG:AG

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

dbSNP: rs80356530 ClinGen: CA143822 OMIM: 605290.0003 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
OPA1		-	-	GRCh38 GRCh37	1353	1554

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Autosomal dominant optic atrophy classic form	Pathogenic/Likely pathogenic (12)	criteria provided, multiple submitters, no conflicts	Aug 17, 2023	RCV000005387.36
Abortive cerebellar ataxia	Pathogenic (1)	no assertion criteria provided	Aug 1, 2011	RCV000210745.9
not provided	Pathogenic (10)	criteria provided, multiple submitters, no conflicts	Nov 1, 2024	RCV000081763.57
Mitochondrial disease	Pathogenic (1)	no assertion criteria provided	Apr 7, 2017	RCV000508703.9
Retinal dystrophy	Pathogenic (1)	criteria provided, single submitter	Oct 12, 2017	RCV001073751.10
Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy	Likely pathogenic (1)	criteria provided, single submitter	-	RCV001542739.10
Abortive cerebellar ataxia Autosomal dominant optic atrophy classic form Glaucoma, normal tension, susceptibility to Mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type) Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy	Pathogenic (1)	criteria provided, single submitter	Jun 11, 2024	RCV002490322.9
3-Methylglutaconic aciduria type 3	Pathogenic (1)	criteria provided, single submitter	Oct 4, 2024	RCV004798716.1
Optic atrophy	Pathogenic (1)	criteria provided, single submitter	Jan 1, 2023	RCV004814831.1
Tip-toe gait	no classifications from unflagged records (1)	no classifications from unflagged records	Sep 5, 2024	RCV003319160.10
OPA1-related disorder	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Mar 18, 2024	RCV004532291.3
See cases	Pathogenic (1)	criteria provided, single submitter	Mar 6, 2023	RCV004584316.1
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Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jan 12, 2017)	criteria provided, single submitter (EGL Classification Definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000228466.5 First in ClinVar: Jun 28, 2015 Last updated: Jul 31, 2019	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=OPA1 Number of individuals with the variant: 23 Zygosity: Single Heterozygote Sex: mixed
Likely pathogenic (Jan 30, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal dominant optic atrophy classic form Affected status: yes Allele origin: unknown	Institute of Medical Molecular Genetics, University of Zurich Accession: SCV001548160.1 First in ClinVar: Mar 28, 2021 Last updated: Mar 28, 2021	Publications: PubMed (1) PubMed: 33546218 Method: WES
Pathogenic (Nov 26, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal dominant optic atrophy classic form Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002579707.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PVS1, PS4, PM2_SUP	Number of individuals with the variant: 1 Sex: male
Pathogenic (Sep 18, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal dominant optic atrophy classic form Affected status: yes Allele origin: maternal	Center of Genomic medicine, Geneva, University Hospital of Geneva Accession: SCV000693465.2 First in ClinVar: Oct 14, 2017 Last updated: Dec 11, 2022	Comment: 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 … (more) 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. (less) Age: 10-19 years Sex: male
Pathogenic (Aug 31, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	OPA1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004120905.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The OPA1 c.2873_2876delTTAG variant is predicted to result in a frameshift and premature protein termination (p.Val958Glyfs3). This variant is also often denoted as c.2708_2711delTTAG (p.Val903Glyfs3) … (more) The OPA1 c.2873_2876delTTAG variant is predicted to result in a frameshift and premature protein termination (p.Val958Glyfs3). This variant is also often denoted as c.2708_2711delTTAG (p.Val903Glyfs3) 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. (less)
Pathogenic (Jan 26, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001591733.3 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (6) PubMed: 11440988‚ 20157015‚ 20952381‚ 25012220‚ 11017079‚ 26385429 Comment: This sequence change creates a premature translational stop signal (p.Val903Glyfs3) in the OPA1 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Val903Glyfs3) 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. (less)
Pathogenic (Jun 11, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy Autosomal dominant optic atrophy classic form Abortive cerebellar ataxia Glaucoma, normal tension, susceptibility to Mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type) Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Fulgent Genetics, Fulgent Genetics Accession: SCV002777553.2 First in ClinVar: Dec 31, 2022 Last updated: Jan 25, 2025
Pathogenic (Oct 12, 2017)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001239311.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Unknown mechanism) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001446520.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Optic atrophy (present) , Optic neuropathy (present) Sex: female
Pathogenic (Jan 04, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Autosomal dominant optic atrophy classic form Affected status: yes Allele origin: unknown	Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris Accession: SCV001519161.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021
Likely pathogenic (-)	criteria provided, single submitter (ACGS Guidelines, 2016) Method: clinical testing	Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy Affected status: yes Allele origin: germline	Genomics England Pilot Project, Genomics England Accession: SCV001760119.1 First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021
Pathogenic (Feb 24, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000252013.10 First in ClinVar: Oct 11, 2015 Last updated: Apr 17, 2019	Comment: 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 … (more) 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) (less)
Pathogenic (Oct 18, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal dominant optic atrophy classic form Affected status: yes Allele origin: germline	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital Accession: SCV001984459.1 First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 Comment: The p.Val903fs variant in the OPA1 gene was previously reported in the heterozygous state in several individuals with optic atrophy (PMID: 11017079 11440989) though penetrance … (more) The p.Val903fs variant in the OPA1 gene was previously reported in the heterozygous state in several individuals with optic atrophy (PMID: 11017079 11440989) though penetrance was incomplete ranging between 43% and 62% (PMID: 11440989). In addition this variant was also identified in the heterozygous state in another patient with optic atrophy plus spastic paraplegia Duane retraction syndrome migraine with atypical aura patent foramen ovale and muscle fibre abnormalities. However this patient's father and sister were unaffected carriers of the same variants again suggesting incomplete penetrance (PMID: 21646330). A mouse model carrying this variant displayed multi-systemic poly-degenerative phenotype with a presentation associating signs of visual failure deafness encephalomyopathy peripheral neuropathy ataxia and cardiomyopathy (PMID: 23250881). The Val903fs variant was also identified in 10/282600 (0.0035% 0 homozygotes) total alleles in the Genome Aggregation Database (gnomAD). This frameshift variant is predicted to alter the protein's amino acid sequence beginning at position 903 and lead to a premature termination codon 3 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary this variant meets our criteria for pathogenicity for dominant optic atrophy with reduced penetrance. (less)
Pathogenic (Mar 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal dominant optic atrophy classic form Affected status: yes Allele origin: germline	3billion Accession: SCV002318897.1 First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022	Publications: PubMed (3) PubMed: 14961560‚ 20417570‚ 11017079 Comment: 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. … (more) 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. (less) Clinical Features: Autistic behavior (present) , Hyperopia, high (present) , Motor delay (present) , Short stature (present) Zygosity: Single Heterozygote
Pathogenic (Aug 17, 2023)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Autosomal dominant optic atrophy classic form (Autosomal dominant inheritance) Affected status: yes Allele origin: maternal	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV004045808.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Number of individuals with the variant: 1 Clinical Features: Optic atrophy (present) , Delayed speech and language development (present)
Pathogenic (Jan 12, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003824243.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Mar 18, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	OPA1-Related Disorders Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV005061372.2 First in ClinVar: Jun 17, 2024 Last updated: Jul 07, 2024	Publications: PubMed (2) PubMed: 17306754‚ 18222991 Comment: 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 … (more) 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. (less)
Pathogenic (Jan 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Optic atrophy Affected status: yes Allele origin: germline	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg Accession: SCV005073536.1 First in ClinVar: Dec 28, 2024 Last updated: Dec 28, 2024
Pathogenic (Mar 06, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	see cases Affected status: yes Allele origin: unknown	Institute of Human Genetics, University Hospital Muenster Accession: SCV002577870.2 First in ClinVar: Oct 08, 2022 Last updated: Jul 07, 2024	Comment: ACMG categories: PVS1,PP1,PP4,PP5 Number of individuals with the variant: 1 Clinical Features: Optic nerve dysplasia (present) Zygosity: Single Heterozygote Age: 20-29 years Sex: male Tissue: blood
Pathogenic (Jun 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal dominant optic atrophy classic form (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV004032248.2 First in ClinVar: Sep 09, 2023 Last updated: Oct 13, 2024	Comment: Criteria applied: PVS1,PS4,PS3_MOD Clinical Features: Myopia (present) , Amblyopia (present) , Astigmatism (present) , Protanopia (present) , Optic atrophy (present) Sex: male
Pathogenic (Jul 17, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal dominant optic atrophy classic form (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005398583.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (8) PubMed: 11440989‚ 17306754‚ 18222991‚ 21636302‚ 25012220‚ 28494813‚ 30165240‚ 31500643 Comment: 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 … (more) 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 (less)
Pathogenic (Oct 04, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Optic atrophy plus syndrome Affected status: yes Allele origin: germline	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital Accession: SCV002818199.2 First in ClinVar: Jan 07, 2023 Last updated: Dec 07, 2024	Comment: PVS1, PM3_Strong, PS3, PM2
Pathogenic (Nov 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001246487.27 First in ClinVar: May 12, 2020 Last updated: Dec 22, 2024	Comment: OPA1: PVS1, PM2, PS4:Moderate Number of individuals with the variant: 8
Pathogenic (Aug 27, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV004226069.2 First in ClinVar: Jan 06, 2024 Last updated: Dec 28, 2024	Publications: PubMed (5) PubMed: 11017079‚ 23250881‚ 32025183‚ 33884488‚ 34242285 Comment: PP1, PM2_moderate, PS4, PVS1
pathogenic (May 03, 2024)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV000614384.5 First in ClinVar: Oct 09, 2016 Last updated: Jan 19, 2025	Publications: PubMed (26) PubMed: 25012220‚ 25641387‚ 24907432‚ 34242285‚ 26385429‚ 11440989‚ 11440988‚ 11017079‚ 20157015‚ 11810270‚ 32025183‚ 12036970‚ 18222991‚ 33884488‚ 21646330‚ 23250881‚ 33546218‚ 16513463‚ 22857269‚ 14961560‚ 15505825‚ 21636302‚ 22042570‚ 20952381‚ 23401657‚ 20659957 Comment: 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 … (more) 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) (less)
Pathogenic (Aug 01, 2011)	no assertion criteria provided Method: literature only	OPTIC ATROPHY 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000025567.3 First in ClinVar: Apr 04, 2013 Last updated: Apr 09, 2016	Publications: PubMed (6) PubMed: 11017079‚ 9490303‚ 9917792‚ 11440989‚ 21636302‚ 25012220 Comment on evidence: In 3 families, Delettre et al. (2000) found that members with autosomal dominant optic atrophy (165500) had a 4-bp deletion in exon 27 of the … (more) In 3 families, Delettre et al. (2000) found that members with autosomal dominant optic atrophy (165500) had a 4-bp deletion in exon 27 of the OPA1 gene, 2708delTTAG, that caused 2 amino acid substitutions (val903 to gly, arg904 to asp) and a premature stop at codon 905. This mutation was present in an asymptomatic carrier in one family but was fully penetrant in the other 2 families. This penetrance was expected since minimally affected patients and asymptomatic carriers (with no detectable optic atrophy on fundus examination) had been described. The 3 families were apparently unrelated, but all originated from the northern French provinces and Belgium. Founder effect had been demonstrated by haplotype studies in the British Isles (Votruba et al., 1998; Johnston et al., 1999). Toomes et al. (2001) haplotyped 8 unrelated individuals with the 2708delTTAG mutation and concluded that this may be a mutation hotspot and not an ancient mutation, thus excluding a major founder effect at the OPA1 locus. A recalculation of the penetrance of this disorder within 2 of 8 families indicated figures as low as 43% and 62% associated with the 2708delTTAG mutation. In 2 sibs with clinical features of Behr syndrome (BEHRS; 210000), Schaaf et al. (2011) identified compound heterozygosity for 2 mutations in the OPA1 gene: 2708delTTAG and I382M (605290.0018). Each parent was heterozygous for 1 of the mutations. The father, who carried the truncating mutation, had mild optic atrophy and bilateral sensorineural hearing loss, whereas the mother, who carried the missense mutation, had myopia, with no evidence of optic atrophy, and mild sensorineural hearing loss. Schaaf et al. (2011) considered the more severe phenotype in the children to be consistent with semidominant inheritance. In an 11-year-old girl with Behr syndrome, Bonneau et al. (2014) identified compound heterozygous mutations in the OPA1 gene: a 4-bp deletion (c.2708_2711) in exon 27, resulting in a frameshift and premature termination (Val903GlyfsTer), and a c.1204G-A transition in exon 12, resulting in a val402-to-met (V402M; 605290.0021) substitution. (less)
Pathogenic (Aug 01, 2011)	no assertion criteria provided Method: literature only	BEHR SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000266834.1 First in ClinVar: Apr 09, 2016 Last updated: Apr 09, 2016	Publications: PubMed (6) PubMed: 11017079‚ 9490303‚ 9917792‚ 11440989‚ 21636302‚ 25012220 Comment on evidence: In 3 families, Delettre et al. (2000) found that members with autosomal dominant optic atrophy (165500) had a 4-bp deletion in exon 27 of the … (more) In 3 families, Delettre et al. (2000) found that members with autosomal dominant optic atrophy (165500) had a 4-bp deletion in exon 27 of the OPA1 gene, 2708delTTAG, that caused 2 amino acid substitutions (val903 to gly, arg904 to asp) and a premature stop at codon 905. This mutation was present in an asymptomatic carrier in one family but was fully penetrant in the other 2 families. This penetrance was expected since minimally affected patients and asymptomatic carriers (with no detectable optic atrophy on fundus examination) had been described. The 3 families were apparently unrelated, but all originated from the northern French provinces and Belgium. Founder effect had been demonstrated by haplotype studies in the British Isles (Votruba et al., 1998; Johnston et al., 1999). Toomes et al. (2001) haplotyped 8 unrelated individuals with the 2708delTTAG mutation and concluded that this may be a mutation hotspot and not an ancient mutation, thus excluding a major founder effect at the OPA1 locus. A recalculation of the penetrance of this disorder within 2 of 8 families indicated figures as low as 43% and 62% associated with the 2708delTTAG mutation. In 2 sibs with clinical features of Behr syndrome (BEHRS; 210000), Schaaf et al. (2011) identified compound heterozygosity for 2 mutations in the OPA1 gene: 2708delTTAG and I382M (605290.0018). Each parent was heterozygous for 1 of the mutations. The father, who carried the truncating mutation, had mild optic atrophy and bilateral sensorineural hearing loss, whereas the mother, who carried the missense mutation, had myopia, with no evidence of optic atrophy, and mild sensorineural hearing loss. Schaaf et al. (2011) considered the more severe phenotype in the children to be consistent with semidominant inheritance. In an 11-year-old girl with Behr syndrome, Bonneau et al. (2014) identified compound heterozygous mutations in the OPA1 gene: a 4-bp deletion (c.2708_2711) in exon 27, resulting in a frameshift and premature termination (Val903GlyfsTer), and a c.1204G-A transition in exon 12, resulting in a val402-to-met (V402M; 605290.0021) substitution. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001921462.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001974149.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Pathogenic (Apr 07, 2017)	no assertion criteria provided Method: clinical testing	Mitochondrial disease Affected status: yes Allele origin: germline	Wellcome Centre for Mitochondrial Research, Newcastle University Accession: SCV000575923.1 First in ClinVar: May 22, 2017 Last updated: May 22, 2017	Publications: PubMed (1) PubMed: 28812649 Number of individuals with the variant: 1
not provided (-)	no classification provided Method: phenotyping only	Autosomal dominant optic atrophy classic form Affected status: yes Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV000606947.2 First in ClinVar: Oct 14, 2017 Last updated: Feb 13, 2022	Comment: 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 … (more) 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. (less) Observation 1: Number of individuals with the variant: 1 Clinical Features: Abnormal lens morphology (present) , Abnormality of vision (present) , Myopia (present) , Hypermetropia (present) , Abnormal optic nerve morphology (present) , Hearing impairment (present) … (more) Abnormal lens morphology (present) , Abnormality of vision (present) , Myopia (present) , Hypermetropia (present) , Abnormal optic nerve morphology (present) , Hearing impairment (present) , Tinnitus (present) , Abnormal large intestine morphology (present) (less) Indication for testing: Diagnostic Age: 50-59 years Sex: female Testing laboratory: GeneDx Date variant was reported to submitter: 2019-11-07 Testing laboratory interpretation: Pathogenic Observation 2: Number of individuals with the variant: 1 Clinical Features: Pregnancy history (present) , Abnormality of eye movement (present) , Abnormality of vision (present) , Myopia (present) , Abnormal optic nerve morphology (present) , Generalized … (more) Pregnancy history (present) , Abnormality of eye movement (present) , Abnormality of vision (present) , Myopia (present) , Abnormal optic nerve morphology (present) , Generalized hypotonia (present) , Anxiety (present) , Depression (present) , Compulsive behaviors (present) , Cafe au lait spots, multiple (present) , Abnormality of the somatic nervous system (present) , Abnormality of the musculature (present) , Abnormal stomach morphology (present) , Abnormal intestine morphology (present) , Abnormal retinal morphology (present) , Gastrointestinal dysmotility (present) (less) Indication for testing: Diagnostic Age: 40-49 years Sex: male Method: Sanger Sequencing Testing laboratory: GeneDx Date variant was reported to submitter: 2016-02-03 Testing laboratory interpretation: Pathogenic
not provided (-)	no classification provided Method: literature only	Autosomal dominant optic atrophy classic form Affected status: yes Allele origin: germline	GeneReviews Accession: SCV000041284.3 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: PubMed (1) PubMed: 11440989 BookShelf: NBK1248 BookShelf: NBK1248
Likely pathogenic (Nov 23, 2022)	Flagged submission flagged submission Method: clinical testing Reason: Outlier claim with insufficient supporting evidence Notes: This gene has (...more) Source: ClinGen	Tip-toe gait Affected status: yes Allele origin: germline	Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino Accession: SCV004023198.2 First in ClinVar: Aug 05, 2023 Last updated: Jun 23, 2024	Publications: PubMed (1) PubMed: 37091313 Comment: 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, … (more) 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. (less) Clinical Features: Macrocephaly (present) , Muscular atrophy (present) , Hyperlordosis (present) , Pes cavus (present) , Brachydactyly (present) , Pectus excavatum (present) , limited range of motion … (more) Macrocephaly (present) , Muscular atrophy (present) , Hyperlordosis (present) , Pes cavus (present) , Brachydactyly (present) , Pectus excavatum (present) , limited range of motion of upper ankle (present) (less) Method: Gene panel analysis
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Comment:

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.

Comment:

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.

Comment:

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)

Comment:

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.

Comment:

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.

Comment:

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

Comment:

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)

Comment:

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.

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
NGS-Panel Diagnosis Developed for the Differential Diagnosis of Idiopathic Toe Walking and Its Application for the Investigation of Possible Genetic Causes for the Gait Anomaly.	Pomarino D	Global medical genetics	2023	PMID: 37091313
Mutation spectrum of the OPA1 gene in a large cohort of patients with suspected dominant optic atrophy: Identification and classification of 48 novel variants.	Weisschuh N	PloS one	2021	PMID: 34242285
Pathogenicity evaluation and the genotype-phenotype analysis of OPA1 variants.	Xu X	Molecular genetics and genomics : MGG	2021	PMID: 33884488
Long-Range PCR-Based NGS Applications to Diagnose Mendelian Retinal Diseases.	Maggi J	International journal of molecular sciences	2021	PMID: 33546218
Targeted next-generation sequencing extends the mutational spectrums for OPA1 mutations in Chinese families with optic atrophy.	Wang Y	Molecular vision	2019	PMID: 32025183
OPA1: 516 unique variants and 831 patients registered in an updated centralized Variome database.	Le Roux B	Orphanet journal of rare diseases	2019	PMID: 31500643
Meta-analysis of genotype-phenotype analysis of OPA1 mutations in autosomal dominant optic atrophy.	Ham M	Mitochondrion	2019	PMID: 30165240
Decreased male reproductive success in association with mitochondrial dysfunction.	Martikainen MH	European journal of human genetics : EJHG	2017	PMID: 28812649
Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations.	Nasca A	Orphanet journal of rare diseases	2017	PMID: 28494813
Genotype-phenotype heterogeneity of ganglion cell and inner plexiform layer deficit in autosomal-dominant optic atrophy.	Rönnbäck C	Acta ophthalmologica	2015	PMID: 26385429
Neuroradiological findings expand the phenotype of OPA1-related mitochondrial dysfunction.	Roubertie A	Journal of the neurological sciences	2015	PMID: 25641387
Optic Atrophy Type 1 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.	Adam MP	-	2015	PMID: 20301426
Early-onset Behr syndrome due to compound heterozygous mutations in OPA1.	Bonneau D	Brain : a journal of neurology	2014	PMID: 25012220
Early macular retinal ganglion cell loss in dominant optic atrophy: genotype-phenotype correlation.	Barboni P	American journal of ophthalmology	2014	PMID: 24907432
Mutation survey of the optic atrophy 1 gene in 193 Chinese families with suspected hereditary optic neuropathy.	Chen Y	Molecular vision	2013	PMID: 23401657
The human OPA1delTTAG mutation induces premature age-related systemic neurodegeneration in mouse.	Sarzi E	Brain : a journal of neurology	2012	PMID: 23250881
Dominant optic atrophy in Denmark - report of 15 novel mutations in OPA1, using a strategy with a detection rate of 90%.	Almind GJ	BMC medical genetics	2012	PMID: 22857269
OPA1 mutations in Japanese patients suspected to have autosomal dominant optic atrophy.	Hamahata T	Japanese journal of ophthalmology	2012	PMID: 22042570
Spastic paraplegia in 'dominant optic atrophy plus' phenotype due to OPA1 mutation.	Pretegiani E	Brain : a journal of neurology	2011	PMID: 21646330
Early-onset severe neuromuscular phenotype associated with compound heterozygosity for OPA1 mutations.	Schaaf CP	Molecular genetics and metabolism	2011	PMID: 21636302
OPA1 mutations impair mitochondrial function in both pure and complicated dominant optic atrophy.	Yu-Wai-Man P	Brain : a journal of neurology	2011	PMID: 20952381
Melanopsin retinal ganglion cells are resistant to neurodegeneration in mitochondrial optic neuropathies.	La Morgia C	Brain : a journal of neurology	2010	PMID: 20659957
The prevalence and natural history of dominant optic atrophy due to OPA1 mutations.	Yu-Wai-Man P	Ophthalmology	2010	PMID: 20417570
Multi-system neurological disease is common in patients with OPA1 mutations.	Yu-Wai-Man P	Brain : a journal of neurology	2010	PMID: 20157015
OPA1 mutations associated with dominant optic atrophy impair oxidative phosphorylation and mitochondrial fusion.	Zanna C	Brain : a journal of neurology	2008	PMID: 18222991
Autosomal dominant optic atrophy: penetrance and expressivity in patients with OPA1 mutations.	Cohn AC	American journal of ophthalmology	2007	PMID: 17306754
Novel mutations in the OPA1 gene and associated clinical features in Japanese patients with optic atrophy.	Nakamura M	Ophthalmology	2006	PMID: 16513463
Deficit of in vivo mitochondrial ATP production in OPA1-related dominant optic atrophy.	Lodi R	Annals of neurology	2004	PMID: 15505825
Fourteen novel OPA1 mutations in autosomal dominant optic atrophy including two de novo mutations in sporadic optic atrophy.	Baris O	Human mutation	2003	PMID: 14961560
A comprehensive survey of mutations in the OPA1 gene in patients with autosomal dominant optic atrophy.	Thiselton DL	Investigative ophthalmology & visual science	2002	PMID: 12036970
Mutation spectrum and splicing variants in the OPA1 gene.	Delettre C	Human genetics	2001	PMID: 11810270
Spectrum, frequency and penetrance of OPA1 mutations in dominant optic atrophy.	Toomes C	Human molecular genetics	2001	PMID: 11440989
OPA1 mutations in patients with autosomal dominant optic atrophy and evidence for semi-dominant inheritance.	Pesch UE	Human molecular genetics	2001	PMID: 11440988
Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy.	Delettre C	Nature genetics	2000	PMID: 11017079
Dominant optic atrophy. Refining the clinical diagnostic criteria in light of genetic linkage studies.	Johnston RL	Ophthalmology	1999	PMID: 9917792
Demonstration of a founder effect and fine mapping of dominant optic atrophy locus on 3q28-qter by linkage disequilibrium method: a study of 38 British Isles pedigrees.	Votruba M	Human genetics	1998	PMID: 9490303
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=OPA1	-	-	-	-
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Text-mined citations for rs80356530 ...

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Record last updated Jan 26, 2025

ClinVar Genomic variation as it relates to human health

NM_130837.3(OPA1):c.2873_2876del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs80356530 ...