The L434P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The L434P variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L434P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (N430D, I432V, C435Y, Q437R, D438G/A/V, G439V) have been reported in the Human Gene Mutation Database in association with optic atrophy 1, multiple mitochondrial DNA deletion disorder, optic atrophy with deafness, and optic atrophy with deafness and ataxia (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
ClinVar Genomic variation as it relates to human health
NM_130837.3(OPA1):c.1466T>C (p.Leu489Pro)
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.
(5)
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
Likely pathogenic(2); Uncertain significance(2)
Likely pathogenic(2); Uncertain significance(2)
5
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.1466T>C (p.Leu489Pro)
Variation ID: 432190 Accession: VCV000432190.9
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q29 3: 193643616 (GRCh38) [ NCBI UCSC ] 3: 193361405 (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 Aug 20, 2017 Mar 16, 2024 Dec 13, 2022 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_130837.3:c.1466T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_570850.2:p.Leu489Pro missense NM_001354663.2:c.932T>C NP_001341592.1:p.Leu311Pro missense NM_001354664.2:c.929T>C NP_001341593.1:p.Leu310Pro missense NM_015560.3:c.1301T>C NP_056375.2:p.Leu434Pro missense NM_130831.3:c.1193T>C NP_570844.1:p.Leu398Pro missense NM_130832.3:c.1247T>C NP_570845.1:p.Leu416Pro missense NM_130833.3:c.1304T>C NP_570846.1:p.Leu435Pro missense NM_130834.3:c.1355T>C NP_570847.2:p.Leu452Pro missense NM_130835.3:c.1358T>C NP_570848.1:p.Leu453Pro missense NM_130836.3:c.1412T>C NP_570849.2:p.Leu471Pro missense NC_000003.12:g.193643616T>C NC_000003.11:g.193361405T>C NG_011605.1:g.55473T>C LRG_337:g.55473T>C LRG_337t1:c.1301T>C LRG_337p1:p.Leu434Pro - Protein change
- L434P, L489P, L416P, L398P, L471P, L435P, L452P, L310P, L311P, L453P
- Other names
- -
- Canonical SPDI
- NC_000003.12:193643615:T:C
-
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.
- -
- 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 |
1266 | 1457 | |
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 (4) |
criteria provided, conflicting classifications
|
Dec 13, 2022 | RCV000497888.11 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
Nov 13, 2021 | RCV003984843.2 |
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
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
(Nov 15, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000702813.2
First in ClinVar: Apr 02, 2018 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
|
|
|
Likely pathogenic
(Jun 10, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000589881.2
First in ClinVar: Aug 20, 2017 Last updated: Aug 20, 2017 |
Comment:
The L434P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The L434P … (more)
The L434P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The L434P variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L434P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (N430D, I432V, C435Y, Q437R, D438G/A/V, G439V) have been reported in the Human Gene Mutation Database in association with optic atrophy 1, multiple mitochondrial DNA deletion disorder, optic atrophy with deafness, and optic atrophy with deafness and ataxia (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. (less)
|
|
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Uncertain significance
(Aug 05, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV002771119.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Likely pathogenic
(Dec 13, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004540395.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
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 … (more)
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.Leu434 amino acid residue in OPA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30201499). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 432190). This variant is also known as p.L489P. This missense change has been observed in individuals with clinical features of OPA1-related conditions (PMID: 29952689, 34242285). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 434 of the OPA1 protein (p.Leu434Pro). (less)
|
|
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Likely pathogenic
(Nov 13, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Auditory neuropathy spectrum disorder
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
maternal
|
Department of Otolaryngology, Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University
Accession: SCV004801107.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Family history: yes
Age: 10-19 years
Sex: female
Ethnicity/Population group: Asian
Geographic origin: China
Tissue: Blood
|
Comment:
Comment:
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.Leu434 amino acid residue in OPA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30201499). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 432190). This variant is also known as p.L489P. This missense change has been observed in individuals with clinical features of OPA1-related conditions (PMID: 29952689, 34242285). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 434 of the OPA1 protein (p.Leu434Pro).
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:
The L434P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The L434P variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L434P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (N430D, I432V, C435Y, Q437R, D438G/A/V, G439V) have been reported in the Human Gene Mutation Database in association with optic atrophy 1, multiple mitochondrial DNA deletion disorder, optic atrophy with deafness, and optic atrophy with deafness and ataxia (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Comment:
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.Leu434 amino acid residue in OPA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30201499). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 432190). This variant is also known as p.L489P. This missense change has been observed in individuals with clinical features of OPA1-related conditions (PMID: 29952689, 34242285). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 434 of the OPA1 protein (p.Leu434Pro).
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 |
| Genetic analysis in a cohort of patients with hereditary optic neuropathies in Southwest of China. | Guo H | Mitochondrion | 2019 | PMID: 30201499 |
| Clinical and genetic features of eight Chinese autosomal-dominant optic atrophy pedigrees with six novel OPA1 pathogenic variants. | Li H | Ophthalmic genetics | 2018 | PMID: 29952689 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=OPA1 | - | - | - | - |
Text-mined citations for rs1553877946 ...
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 Sep 29, 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.