ClinVar Genomic variation as it relates to human health
NM_130837.3(OPA1):c.1800C>G (p.Ser600Arg)
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
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NM_130837.3(OPA1):c.1800C>G (p.Ser600Arg)
Variation ID: 30461 Accession: VCV000030461.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q29 3: 193647110 (GRCh38) [ NCBI UCSC ] 3: 193364899 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Aug 22, 2016 Feb 14, 2024 Nov 22, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_130837.3:c.1800C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_570850.2:p.Ser600Arg missense NM_001354663.2:c.1266C>G NP_001341592.1:p.Ser422Arg missense NM_001354664.2:c.1263C>G NP_001341593.1:p.Ser421Arg missense NM_015560.3:c.1635C>G NP_056375.2:p.Ser545Arg missense NM_130831.3:c.1527C>G NP_570844.1:p.Ser509Arg missense NM_130832.3:c.1581C>G NP_570845.1:p.Ser527Arg missense NM_130833.3:c.1638C>G NP_570846.1:p.Ser546Arg missense NM_130834.3:c.1689C>G NP_570847.2:p.Ser563Arg missense NM_130835.3:c.1692C>G NP_570848.1:p.Ser564Arg missense NM_130836.3:c.1746C>G NP_570849.2:p.Ser582Arg missense NC_000003.12:g.193647110C>G NC_000003.11:g.193364899C>G NG_011605.1:g.58967C>G LRG_337:g.58967C>G LRG_337t1:c.1635C>G LRG_337p1:p.Ser545Arg - Protein change
- S545R, S600R, S421R, S564R, S582R, S422R, S527R, S546R, S509R, S563R
- Other names
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- Canonical SPDI
- NC_000003.12:193647109:C:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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LOC126806913 | - | - | - | GRCh38 | - | 62 |
OPA1 | - | - |
GRCh38 GRCh37 |
1232 | 1420 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
no assertion criteria provided
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Mar 1, 2010 | RCV000023415.4 | |
Pathogenic (1) |
no assertion criteria provided
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Apr 7, 2017 | RCV000508898.1 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 19, 2022 | RCV001659726.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 22, 2022 | RCV002464072.2 |
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
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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
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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
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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. |
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Pathogenic
(Nov 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant optic atrophy classic form
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Centre for Inherited Metabolic Diseases, Karolinska University Hospital
Accession: SCV002605369.1
First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022 |
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Pathogenic
(Jan 25, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics Inc
Accession: SCV001880546.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
Comment:
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant appears to segregate with disease in at least one family. Assessment … (more)
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant appears to segregate with disease in at least one family. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant reduced the protein's GTP hydrolysis activity (PMID: 20185555, 30293569). (less)
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Pathogenic
(Oct 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002236722.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more)
For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on OPA1 protein function. ClinVar contains an entry for this variant (Variation ID: 30461). This missense change has been observed in individual(s) with autosomal dominant OPA1-related conditions (PMID: 18065439, 18158317). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 545 of the OPA1 protein (p.Ser545Arg). (less)
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Pathogenic
(Apr 07, 2017)
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no assertion criteria provided
Method: clinical testing
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Mitochondrial disease
Affected status: yes
Allele origin:
germline
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Wellcome Centre for Mitochondrial Research, Newcastle University
Accession: SCV000575922.1
First in ClinVar: May 22, 2017 Last updated: May 22, 2017 |
Number of individuals with the variant: 2
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Pathogenic
(Mar 01, 2010)
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no assertion criteria provided
Method: literature only
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OPTIC ATROPHY WITH OR WITHOUT DEAFNESS, OPHTHALMOPLEGIA, MYOPATHY, ATAXIA, AND NEUROPATHY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000044706.3
First in ClinVar: Apr 04, 2013 Last updated: Feb 20, 2021 |
Comment on evidence:
In 7 affected members of a 3-generation family with optic atrophy, ataxia, and progressive external ophthalmoplegia (125250), Hudson et al. (2008) identified heterozygosity for a … (more)
In 7 affected members of a 3-generation family with optic atrophy, ataxia, and progressive external ophthalmoplegia (125250), Hudson et al. (2008) identified heterozygosity for a 1635C-G transversion in exon 17 of the OPA1 gene, resulting in a ser545-to-arg (S545R) substitution in the GTPase domain. Three patients had deafness with onset in the third or fourth decade, and 3 patients had neuropathy and myopathy. In 3 affected members of an Austrian family with optic atrophy, deafness, progressive external ophthalmoplegia, ataxia, and neuropathy (125250), Yu-Wai-Man et al. (2010) identified a heterozygous S545R mutation, which they noted was in the dynamin domain of the protein. Two patients in their thirties had deafness, whereas an older family member in her sixties did not have deafness. The authors also identified the S545R mutation in a 30-year-old French man with optic atrophy, deafness, ataxia, myopathy, and neuropathy. (less)
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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 |
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Deciphering OPA1 mutations pathogenicity by combined analysis of human, mouse and yeast cell models. | Del Dotto V | Biochimica et biophysica acta. Molecular basis of disease | 2018 | PMID: 30293569 |
Decreased male reproductive success in association with mitochondrial dysfunction. | Martikainen MH | European journal of human genetics : EJHG | 2017 | PMID: 28812649 |
Autophagy controls the pathogenicity of OPA1 mutations in dominant optic atrophy. | Kane MS | Journal of cellular and molecular medicine | 2017 | PMID: 28378518 |
Standardized mitochondrial analysis gives new insights into mitochondrial dynamics and OPA1 function. | Chevrollier A | The international journal of biochemistry & cell biology | 2012 | PMID: 22433900 |
The prevalence and natural history of dominant optic atrophy due to OPA1 mutations. | Yu-Wai-Man P | Ophthalmology | 2010 | PMID: 20417570 |
OPA1 disease alleles causing dominant optic atrophy have defects in cardiolipin-stimulated GTP hydrolysis and membrane tubulation. | Ban T | Human molecular genetics | 2010 | PMID: 20185555 |
Multi-system neurological disease is common in patients with OPA1 mutations. | Yu-Wai-Man P | Brain : a journal of neurology | 2010 | PMID: 20157015 |
Molecular screening of 980 cases of suspected hereditary optic neuropathy with a report on 77 novel OPA1 mutations. | Ferré M | Human mutation | 2009 | PMID: 19319978 |
OPA1 mutations induce mitochondrial DNA instability and optic atrophy 'plus' phenotypes. | Amati-Bonneau P | Brain : a journal of neurology | 2008 | PMID: 18158317 |
Mutation of OPA1 causes dominant optic atrophy with external ophthalmoplegia, ataxia, deafness and multiple mitochondrial DNA deletions: a novel disorder of mtDNA maintenance. | Hudson G | Brain : a journal of neurology | 2008 | PMID: 18065439 |
Text-mined citations for rs398124298 ...
HelpRecord last updated Feb 14, 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.