This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
ClinVar Genomic variation as it relates to human health
NM_130837.3(OPA1):c.2962G>A (p.Val988Ile)
Germline
Classification
Help
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.
(6)
Help
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.
Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(2); Uncertain significance(3)
Pathogenic(1); Likely pathogenic(2); Uncertain significance(3)
6
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_130837.3(OPA1):c.2962G>A (p.Val988Ile)
Variation ID: 427152 Accession: VCV000427152.14
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3q29 3: 193667259 (GRCh38) [ NCBI UCSC ] 3: 193385048 (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 May 22, 2017 Nov 24, 2024 Jun 4, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_130837.3:c.2962G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_570850.2:p.Val988Ile missense NM_001354663.2:c.2428G>A NP_001341592.1:p.Val810Ile missense NM_001354664.2:c.2425G>A NP_001341593.1:p.Val809Ile missense NM_015560.3:c.2797G>A NP_056375.2:p.Val933Ile missense NM_130831.3:c.2689G>A NP_570844.1:p.Val897Ile missense NM_130832.3:c.2743G>A NP_570845.1:p.Val915Ile missense NM_130833.3:c.2800G>A NP_570846.1:p.Val934Ile missense NM_130834.3:c.2851G>A NP_570847.2:p.Val951Ile missense NM_130835.3:c.2854G>A NP_570848.1:p.Val952Ile missense NM_130836.3:c.2908G>A NP_570849.2:p.Val970Ile missense NC_000003.12:g.193667259G>A NC_000003.11:g.193385048G>A NG_011605.1:g.79116G>A LRG_337:g.79116G>A LRG_337t1:c.2797G>A LRG_337p1:p.Val933Ile - Protein change
- V933I, V988I, V970I, V810I, V915I, V952I, V809I, V934I, V897I, V951I
- Other names
-
p.Val933Ile
- Canonical SPDI
- NC_000003.12:193667258:G:A
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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.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
- Links
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 |
1279 | 1471 | |
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Jul 20, 2023 | RCV000489553.10 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Oct 18, 2022 | RCV002307519.1 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Sep 28, 2017 | RCV001146349.4 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 4, 2024 | RCV004584730.1 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Sep 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal dominant optic atrophy classic form
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001307090.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
|
|
|
Uncertain significance
(Oct 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002600559.1
First in ClinVar: Nov 19, 2022 Last updated: Nov 19, 2022 |
Comment:
Variant summary: OPA1 c.2797G>A (p.Val933Ile) results in a conservative amino acid change located in the C-terminal domain (IPR045817) of the encoded protein sequence. Four of … (more)
Variant summary: OPA1 c.2797G>A (p.Val933Ile) results in a conservative amino acid change located in the C-terminal domain (IPR045817) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251456 control chromosomes (gnomAD). c.2797G>A has been reported in the literature in at least two related individuals affected with autosomal dominant optic atrophy (e.g. Barboni_2010, Rocca_2015, Cascavilla_2018, Weisschuh_2021). These data indicate that the variant may be associated with disease. A different variant affecting the same codon has been reported in association with Spastic ataxic syndrome with peripheral neuropathy in HGMD (p.V933F). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Two laboratories classified the variant as VUS and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
|
|
|
Uncertain significance
(Jul 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000577786.6
First in ClinVar: May 22, 2017 Last updated: Mar 04, 2023 |
Comment:
Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This … (more)
Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20417568, 31589614, 28926202, 34242285, 25794858) (less)
|
|
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Likely pathogenic
(Aug 16, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002286552.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 427152). This missense change has been observed in individuals with autosomal dominant OPA1-related conditions (PMID: 20417568, … (more)
ClinVar contains an entry for this variant (Variation ID: 427152). This missense change has been observed in individuals with autosomal dominant OPA1-related conditions (PMID: 20417568, 25794858). This variant is present in population databases (rs375733283, gnomAD 0.0008%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 933 of the OPA1 protein (p.Val933Ile). 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) performed at Invitae indicates that this missense variant is expected to disrupt OPA1 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Val933 amino acid residue in OPA1. Other variant(s) that disrupt this residue have been observed in individuals with OPA1-related conditions (PMID: 28494813), which suggests that this may be a clinically significant amino acid residue. (less)
|
|
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Pathogenic
(Jun 04, 2024)
|
criteria provided, single submitter
Method: research
|
Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy
Affected status: yes
Allele origin:
germline
|
Laboratory of Prof. Karen Avraham, Tel Aviv University
Accession: SCV005073782.1
First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024
Comment:
Autosomal dominant, high-tone normal-to-severe HL
|
Comment:
Pathgenic by Deafness Variation Database according to PMID:20417568, 25794858, 28926202
Number of individuals with the variant: 1
Ethnicity/Population group: Jewish
Geographic origin: Israel
Testing laboratory: Prof. Karen Avraham, Tel Aviv University, Israel
Date variant was reported to submitter: 2024-06-04
|
|
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Likely pathogenic
(Jul 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV005413630.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
PM2_moderate, PM5, PS4
Number of individuals with the variant: 1
|
Comment:
Comment:
Variant summary: OPA1 c.2797G>A (p.Val933Ile) results in a conservative amino acid change located in the C-terminal domain (IPR045817) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251456 control chromosomes (gnomAD). c.2797G>A has been reported in the literature in at least two related individuals affected with autosomal dominant optic atrophy (e.g. Barboni_2010, Rocca_2015, Cascavilla_2018, Weisschuh_2021). These data indicate that the variant may be associated with disease. A different variant affecting the same codon has been reported in association with Spastic ataxic syndrome with peripheral neuropathy in HGMD (p.V933F). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Two laboratories classified the variant as VUS and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Comment:
Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20417568, 31589614, 28926202, 34242285, 25794858)
Comment:
ClinVar contains an entry for this variant (Variation ID: 427152). This missense change has been observed in individuals with autosomal dominant OPA1-related conditions (PMID: 20417568, 25794858). This variant is present in population databases (rs375733283, gnomAD 0.0008%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 933 of the OPA1 protein (p.Val933Ile). 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) performed at Invitae indicates that this missense variant is expected to disrupt OPA1 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Val933 amino acid residue in OPA1. Other variant(s) that disrupt this residue have been observed in individuals with OPA1-related conditions (PMID: 28494813), which suggests that this may be a clinically significant amino acid residue.
Comment:
Pathgenic by Deafness Variation Database according to PMID:20417568, 25794858, 28926202
Comment:
PM2_moderate, PM5, PS4
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:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Comment:
Variant summary: OPA1 c.2797G>A (p.Val933Ile) results in a conservative amino acid change located in the C-terminal domain (IPR045817) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251456 control chromosomes (gnomAD). c.2797G>A has been reported in the literature in at least two related individuals affected with autosomal dominant optic atrophy (e.g. Barboni_2010, Rocca_2015, Cascavilla_2018, Weisschuh_2021). These data indicate that the variant may be associated with disease. A different variant affecting the same codon has been reported in association with Spastic ataxic syndrome with peripheral neuropathy in HGMD (p.V933F). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Two laboratories classified the variant as VUS and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Comment:
Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20417568, 31589614, 28926202, 34242285, 25794858)
Comment:
ClinVar contains an entry for this variant (Variation ID: 427152). This missense change has been observed in individuals with autosomal dominant OPA1-related conditions (PMID: 20417568, 25794858). This variant is present in population databases (rs375733283, gnomAD 0.0008%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 933 of the OPA1 protein (p.Val933Ile). 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) performed at Invitae indicates that this missense variant is expected to disrupt OPA1 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Val933 amino acid residue in OPA1. Other variant(s) that disrupt this residue have been observed in individuals with OPA1-related conditions (PMID: 28494813), which suggests that this may be a clinically significant amino acid residue.
Comment:
Pathgenic by Deafness Variation Database according to PMID:20417568, 25794858, 28926202
Comment:
PM2_moderate, PM5, PS4
Citations for germline classification of this variant
Help| Title | 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 |
| Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes. | Capalbo A | PLoS genetics | 2019 | PMID: 31589614 |
| Retinal dysfunction characterizes subtypes of dominant optic atrophy. | Cascavilla ML | Acta ophthalmologica | 2018 | PMID: 28926202 |
| 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 |
| Distributed abnormalities of brain white matter architecture in patients with dominant optic atrophy and OPA1 mutations. | Rocca MA | Journal of neurology | 2015 | PMID: 25794858 |
| OPA1 mutations associated with dominant optic atrophy influence optic nerve head size. | Barboni P | Ophthalmology | 2010 | PMID: 20417568 |
Text-mined citations for rs375733283 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 30, 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.