ClinVar Genomic variation as it relates to human health
NM_130837.3(OPA1):c.2873_2876del
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_130837.3(OPA1):c.2873_2876del
Variation ID: 5082 Accession: VCV000005082.52
- 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 May 12, 2024 Jan 26, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_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_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 - Protein change
- Other names
- p.Val903Glyfs*3
- Canonical SPDI
- NC_000003.12:193667167:AGTTAG:AG
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe 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.
-
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 | ||
---|---|---|---|---|---|---|
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 |
1234 | 1423 |
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. |
---|---|---|---|---|
Pathogenic/Likely pathogenic (11) |
criteria provided, multiple submitters, no conflicts
|
Aug 23, 2023 | RCV000005387.31 | |
Pathogenic (11) |
criteria provided, multiple submitters, no conflicts
|
Jan 26, 2024 | RCV000081763.46 | |
Pathogenic (1) |
no assertion criteria provided
|
Aug 1, 2011 | RCV000210745.9 | |
Pathogenic (1) |
no assertion criteria provided
|
Apr 7, 2017 | RCV000508703.9 | |
Pathogenic (1) |
criteria provided, single submitter
|
Oct 12, 2017 | RCV001073751.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
- | RCV001542739.10 | |
Pathogenic (1) |
criteria provided, single submitter
|
Oct 4, 2021 | RCV002287324.8 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jul 22, 2021 | RCV002490322.8 | |
Likely pathogenic (1) |
no assertion criteria provided
|
Nov 23, 2022 | RCV003319160.8 | |
OPA1-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Aug 31, 2023 | RCV004532291.1 |
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
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 |
Number of individuals with the variant: 23
Sex: mixed
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
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
(Aug 23, 2023)
|
criteria provided, single submitter
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: SCV004032248.1
First in ClinVar: Sep 09, 2023 Last updated: Sep 09, 2023 |
Comment:
Criteria applied: PVS1,PS4,PS3_MOD
Clinical Features:
Optic atrophy (present)
Sex: male
|
|
Pathogenic
(Aug 31, 2023)
|
criteria provided, single submitter
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.Val958Glyfs*3). This variant is also often denoted as c.2708_2711delTTAG (p.Val903Glyfs*3) … (more)
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. (less)
|
|
Pathogenic
(Oct 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226069.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP1, PS4, PVS1
Number of individuals with the variant: 3
|
|
Pathogenic
(Jan 12, 2022)
|
criteria provided, single submitter
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
(Jul 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001246487.21
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 7
|
|
Pathogenic
(Oct 12, 2017)
|
criteria provided, single submitter
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
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
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
(Jan 30, 2021)
|
criteria provided, single submitter
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 |
Method: WES
|
|
Pathogenic
(Feb 24, 2020)
|
criteria provided, single submitter
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
(Mar 22, 2022)
|
criteria provided, single submitter
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 |
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)
|
|
Pathogenic
(Oct 04, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Optic nerve dysplasia
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University Hospital Muenster
Accession: SCV002577870.1
First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022 |
Comment:
ACMG categories: PVS1,PP1,PP4,PP5
Number of individuals with the variant: 1
Clinical Features:
Optic nerve dysplasia (present)
Age: 20-29 years
Sex: male
Tissue: blood
|
|
Pathogenic
(Nov 26, 2021)
|
criteria provided, single submitter
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
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
(Jul 22, 2021)
|
criteria provided, single submitter
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)
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002777553.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
Pathogenic
(Dec 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital
Accession: SCV002818199.1
First in ClinVar: Jan 07, 2023 Last updated: Jan 07, 2023 |
|
|
Pathogenic
(Aug 17, 2023)
|
criteria provided, single submitter
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
(Dec 07, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV000614384.4
First in ClinVar: Oct 09, 2016 Last updated: Jan 26, 2024 |
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) This variant occurs with an alternate explanation for disease significantly less often than expected, suggesting this variant may be associated with disease. (less)
|
|
Pathogenic
(Jan 26, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001591733.3
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
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 … (more)
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. (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 |
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
(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 |
Number of individuals with the variant: 1
|
|
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
(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 |
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 |
|
|
Likely pathogenic
(Nov 23, 2022)
|
no assertion criteria provided
Method: clinical testing
|
Tip-toe gait
Affected status: yes
Allele origin:
germline
|
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino
Accession: SCV004023198.1
First in ClinVar: Aug 05, 2023 Last updated: Aug 05, 2023 |
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
|
|
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 |
|
|
Pathogenic
(Oct 18, 2020)
|
Flagged submission
flagged submission
Method: clinical testing
Reason: This record appears to be redundant with a more recent record from the same submitter.
Notes: SCV001984459 appears to be redundant with SCV002818199.
(less)
Notes: SCV001984459 appears to
(...more)
Source: NCBI
|
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)
|
|
|
click to load more click to collapse | |||||
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
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 |
Decreased male reproductive success in association with mitochondrial dysfunction. | Martikainen MH | European journal of human genetics : EJHG | 2017 | PMID: 28812649 |
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 |
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 | - | - | - | - |
click to load more click to collapse |
Text-mined citations for rs80356530 ...
HelpRecord last updated May 27, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.