ClinVar Genomic variation as it relates to human health
NC_012920.1(MT-ND1):m.3460G>A
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NC_012920.1(MT-ND1):m.3460G>A
Variation ID: 9722 Accession: VCV000009722.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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MT: 3460 (GRCh38) [ NCBI UCSC ] MT: 3460 (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 Oct 3, 2013 Aug 5, 2023 Apr 25, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNC_012920.1:m.3460G>A - Protein change
- Other names
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- Canonical SPDI
- NC_012920.1:3459:G:A
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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
Help
The frequency of the allele represented by this VCV record.
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- Links
- ClinGen: CA120646
- Genetic Testing Registry (GTR): GTR000500596
- Genetic Testing Registry (GTR): GTR000501208
- Genetic Testing Registry (GTR): GTR000522506
- Genetic Testing Registry (GTR): GTR000556567
- Genetic Testing Registry (GTR): GTR000558136
- Genetic Testing Registry (GTR): GTR000591967
- Genetic Testing Registry (GTR): GTR000591969
- Genetic Testing Registry (GTR): GTR000591975
- Genetic Testing Registry (GTR): GTR000591976
- OMIM: 516000.0001
- dbSNP: rs199476118
- VarSome
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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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
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. |
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MT-ND1 | - | - | GRCh38 | 177 | 179 |
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. |
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Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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May 4, 2022 | RCV000010370.12 | |
not provided (1) |
no classification provided
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- | RCV000143998.5 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 23, 2020 | RCV000757484.9 | |
MITOCHONDRIAL COMPLEX I DEFICIENCY, MITOCHONDRIAL TYPE 3
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Pathogenic (1) |
no assertion criteria provided
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Jul 10, 2007 | RCV000735416.1 |
Pathogenic (1) |
reviewed by expert panel
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Apr 25, 2023 | RCV003319165.1 |
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. |
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Pathogenic
(Apr 25, 2023)
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reviewed by expert panel
Method: curation
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Mitochondrial disease
(Mitochondrial inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen
FDA Recognized Database
Accession: SCV004023282.1 First in ClinVar: Aug 05, 2023 Last updated: Aug 05, 2023 |
Comment:
The m.3460G>A (p.A52T) variant in MT-ND1 has been reported in affected individuals from more than 50 kindreds (PS4, PMIDs: 1928099, 1674640, 7629530, 1734726, 1550131, 8496715, … (more)
The m.3460G>A (p.A52T) variant in MT-ND1 has been reported in affected individuals from more than 50 kindreds (PS4, PMIDs: 1928099, 1674640, 7629530, 1734726, 1550131, 8496715, 8024249, 8556281, 8571959, 12205655, 11906302, 12807863, 12518276, 16738010, 17122117, 18216301, 18562849, 20232220, 21887510, 25338955, 25053773, 28314831, 30053855, 30591017). While this variant is one of the three most common variants associated with Leber Hereditary Optic Neuropathy (LHON; PMID: 20301353), affected individuals can also have other features. Indeed, several individuals have been reported with multiple sclerosis. Other features have been variably seen in affected individuals including sensorineural hearing loss, auditory neuropathy, epilepsy, migraines, Parkinsonism, dystonia, Leigh syndrome, spinal cord lesions, myoclonus, myopathy, hypertension, high triglycerides, diabetes, and cardiac involvement. Testing excluding separate etiologies for these features has been limited. Heteroplasmy levels in affected individuals ranged from 58% to homoplasmy. Age of onset varied from four years old to 75 years old. This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMIDs: 1734726, 8571959, 11906302). There is one reported de novo occurrence to our knowledge (PM6_supporting; PMID: 12518276). This variant is present in the healthy population, which is to be expected given the known reduced penetrance of this variant. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.86 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Extensive cybrid studies supported the functional impact of this variant, as do E. coli and mouse studies (PS3_moderate PMIDs: 35383288, 22079202, 15720387, 15883259, 15342361, 10976107). In summary, this variant meets criteria to be classified as pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on April 25, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4, PP1_moderate, PM6_supporting, PP3, PS3_moderate. (less)
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Pathogenic
(Nov 22, 2017)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000885731.1
First in ClinVar: Feb 18, 2019 Last updated: Feb 18, 2019 |
Comment:
m.3460G>A is one of a small number of primary variants which are causative of Leber hereditary optic neuropathy (LHON; MIM: 535000; Howell 1992). It is … (more)
m.3460G>A is one of a small number of primary variants which are causative of Leber hereditary optic neuropathy (LHON; MIM: 535000; Howell 1992). It is estimated that 15%-25% of LHON families carry the g.3460G>A variant (Howell 1991). (less)
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Pathogenic
(Oct 17, 2019)
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criteria provided, single submitter
Method: clinical testing
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Leber optic atrophy
Affected status: unknown
Allele origin:
germline
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Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine
Accession: SCV000996688.1
First in ClinVar: Nov 02, 2019 Last updated: Nov 02, 2019 |
Comment:
The NC_012920.1:m.3460G>A (YP_003024026.1:p.Ala52Thr) variant in MTND1 gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the … (more)
The NC_012920.1:m.3460G>A (YP_003024026.1:p.Ala52Thr) variant in MTND1 gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PS1, PS3 (less)
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Mitochondrial inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447466.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Spastic paraplegia (present) , Leber optic atrophy (present)
Sex: male
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Pathogenic
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Leber optic atrophy
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002517662.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Pathogenic
(Jul 10, 2007)
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no assertion criteria provided
Method: literature only
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MITOCHONDRIAL COMPLEX I DEFICIENCY, MITOCHONDRIAL TYPE 3
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000863528.1
First in ClinVar: Dec 17, 2018 Last updated: Dec 17, 2018 |
Comment on evidence:
Leber Optic Atrophy The 3460G-A transition in the MTND1 gene converts the modestly conserved alanine 52 to a threonine (A52T). It is sufficient by itself … (more)
Leber Optic Atrophy The 3460G-A transition in the MTND1 gene converts the modestly conserved alanine 52 to a threonine (A52T). It is sufficient by itself to cause LHON (535000), is found in about 15% of Caucasian patients but not controls, has arisen on a variety of genetic backgrounds, can be heteroplasmic, results in vision loss in 14 to 40% of maternal relatives and 33 to 67% of males, and has a 22% visual recovery rate (Brown et al., 1992; Howell et al., 1991; Howell et al., 1992; Huoponen et al., 1991; Johns, 1992; Johns et al., 1992; Majander et al., 1991; Paulus et al., 1993) Wong et al. (2002) created cybrids using a neuronal precursor cell line, NT2, containing mitochondria from patient lymphoblasts bearing the most common LHON mutation, 11778 (516003.0001), and the most severe LHON mutation, 3460. The undifferentiated LHON-NT2 mutant cells were not significantly different from the parental cell control in terms of mtDNA/nDNA ratio, mitochondrial membrane potential, reactive oxygen species (ROS) production, or the ability to reduce the reagent Alamar blue. Differentiation of NT2s resulted in a neuronal morphology, a neuron-specific pattern of gene expression, and a 3-fold reduction in mtDNA/nDNA ratio in both mutant and control cells; however, the differentiation protocol yielded 30% less LHON cells than controls, indicating either a decreased proliferative potential or increased cell death of the LHON-NT2 cells. Differentiation of the cells to the neuronal form also resulted in significant increases in ROS production in the LHON-NT2 neurons versus controls, which was abolished by rotenone (a specific inhibitor of complex I). Wong et al. (2002) inferred that the LHON genotype may require a differentiated neuronal environment in order to induce increased mitochondrial ROS, which may be the cause of the reduced NT2 yield. They hypothesized that the LHON degenerative phenotype may be the result of an increase in mitochondrial superoxide which is caused by the LHON mutations, possibly mediated through neuron-specific alterations in complex I structure. Jaros et al. (2007) reported a 39-year-old woman with severe complicated LHON who developed progressive gait and sensory disturbances 5 years after onset of subacute bilateral visual failure. Visual symptoms included loss of acuity, central scotomata, optic atrophy, and nystagmus. She also had symmetric pyramidal-pattern lower limb weakness, hyperreflexia, and distal loss of vibratory sensation. Brain MRI showed symmetric high T2 signals in the substantia nigra, pons, and dorsal columns of the spinal cord. After an unexpected death, postmortem examination showed myelin loss and macrophage activation in the posterior columns of the upper spinal cord and neurodegeneration at multiple levels. Molecular analysis detected a homoplasmic 3460G-A mutation in blood and spinal cord. Her mtDNA haplotype H and HLA-DR8 status did not explain the severe phenotype. Mitochondrial Complex I Deficiency, Mitochondrial Type 3 Hinttala et al. (2006) identified a homoplasmic 3460G-A mutation in skeletal muscle from an 18-year-old woman with severe mitochondrial complex I deficiency (MC1DM3) manifest as a progressive myopathy starting at age 10 years. She was wheelchair-bound with normal mental functioning. Her younger brother developed classic LHON. (less)
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Pathogenic
(Jul 10, 2007)
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no assertion criteria provided
Method: literature only
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LEBER OPTIC ATROPHY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000030596.4
First in ClinVar: Apr 04, 2013 Last updated: Dec 16, 2018 |
Comment on evidence:
Leber Optic Atrophy The 3460G-A transition in the MTND1 gene converts the modestly conserved alanine 52 to a threonine (A52T). It is sufficient by itself … (more)
Leber Optic Atrophy The 3460G-A transition in the MTND1 gene converts the modestly conserved alanine 52 to a threonine (A52T). It is sufficient by itself to cause LHON (535000), is found in about 15% of Caucasian patients but not controls, has arisen on a variety of genetic backgrounds, can be heteroplasmic, results in vision loss in 14 to 40% of maternal relatives and 33 to 67% of males, and has a 22% visual recovery rate (Brown et al., 1992; Howell et al., 1991; Howell et al., 1992; Huoponen et al., 1991; Johns, 1992; Johns et al., 1992; Majander et al., 1991; Paulus et al., 1993) Wong et al. (2002) created cybrids using a neuronal precursor cell line, NT2, containing mitochondria from patient lymphoblasts bearing the most common LHON mutation, 11778 (516003.0001), and the most severe LHON mutation, 3460. The undifferentiated LHON-NT2 mutant cells were not significantly different from the parental cell control in terms of mtDNA/nDNA ratio, mitochondrial membrane potential, reactive oxygen species (ROS) production, or the ability to reduce the reagent Alamar blue. Differentiation of NT2s resulted in a neuronal morphology, a neuron-specific pattern of gene expression, and a 3-fold reduction in mtDNA/nDNA ratio in both mutant and control cells; however, the differentiation protocol yielded 30% less LHON cells than controls, indicating either a decreased proliferative potential or increased cell death of the LHON-NT2 cells. Differentiation of the cells to the neuronal form also resulted in significant increases in ROS production in the LHON-NT2 neurons versus controls, which was abolished by rotenone (a specific inhibitor of complex I). Wong et al. (2002) inferred that the LHON genotype may require a differentiated neuronal environment in order to induce increased mitochondrial ROS, which may be the cause of the reduced NT2 yield. They hypothesized that the LHON degenerative phenotype may be the result of an increase in mitochondrial superoxide which is caused by the LHON mutations, possibly mediated through neuron-specific alterations in complex I structure. Jaros et al. (2007) reported a 39-year-old woman with severe complicated LHON who developed progressive gait and sensory disturbances 5 years after onset of subacute bilateral visual failure. Visual symptoms included loss of acuity, central scotomata, optic atrophy, and nystagmus. She also had symmetric pyramidal-pattern lower limb weakness, hyperreflexia, and distal loss of vibratory sensation. Brain MRI showed symmetric high T2 signals in the substantia nigra, pons, and dorsal columns of the spinal cord. After an unexpected death, postmortem examination showed myelin loss and macrophage activation in the posterior columns of the upper spinal cord and neurodegeneration at multiple levels. Molecular analysis detected a homoplasmic 3460G-A mutation in blood and spinal cord. Her mtDNA haplotype H and HLA-DR8 status did not explain the severe phenotype. Mitochondrial Complex I Deficiency, Mitochondrial Type 3 Hinttala et al. (2006) identified a homoplasmic 3460G-A mutation in skeletal muscle from an 18-year-old woman with severe mitochondrial complex I deficiency (MC1DM3) manifest as a progressive myopathy starting at age 10 years. She was wheelchair-bound with normal mental functioning. Her younger brother developed classic LHON. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Leber optic atrophy
Affected status: yes
Allele origin:
germline
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Genomics England Pilot Project, Genomics England
Accession: SCV001760534.1
First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Leber optic atrophy
Affected status: unknown
Allele origin:
maternal
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GeneReviews
Accession: SCV000086632.3
First in ClinVar: Oct 03, 2013 Last updated: Oct 01, 2022 |
Comment:
This variant is one of the three most common causes of LHON.
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not provided
(-)
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no classification provided
Method: literature only
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Leigh syndrome
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000188884.5
First in ClinVar: Sep 09, 2014 Last updated: Oct 01, 2022 |
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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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Mitochondrial DNA-Associated Leigh Syndrome Spectrum. | Adam MP | - | 2024 | PMID: 20301352 |
Gene therapy restores mitochondrial function and protects retinal ganglion cells in optic neuropathy induced by a mito-targeted mutant ND1 gene. | Liu Y | Gene therapy | 2022 | PMID: 35383288 |
Leber Hereditary Optic Neuropathy. | Adam MP | - | 2021 | PMID: 20301353 |
Clinical utility gene card for: inherited optic neuropathies including next-generation sequencing-based approaches. | Jurkute N | European journal of human genetics : EJHG | 2019 | PMID: 30143805 |
LHON/MELAS overlap mutation in ND1 subunit of mitochondrial complex I affects ubiquinone binding as revealed by modeling in Escherichia coli NDH-1. | Pätsi J | Biochimica et biophysica acta | 2012 | PMID: 22079202 |
Primary spinal cord neurodegeneration in Leber hereditary optic neuropathy. | Jaros E | Neurology | 2007 | PMID: 17620555 |
Analysis of mitochondrial DNA sequences in patients with isolated or combined oxidative phosphorylation system deficiency. | Hinttala R | Journal of medical genetics | 2006 | PMID: 16738010 |
Severe impairment of complex I-driven adenosine triphosphate synthesis in leber hereditary optic neuropathy cybrids. | Baracca A | Archives of neurology | 2005 | PMID: 15883259 |
Antioxidant defences in cybrids harboring mtDNA mutations associated with Leber's hereditary optic neuropathy. | Floreani M | The FEBS journal | 2005 | PMID: 15720387 |
Leber hereditary optic neuropathy mtDNA mutations disrupt glutamate transport in cybrid cell lines. | Beretta S | Brain : a journal of neurology | 2004 | PMID: 15342361 |
Differentiation-specific effects of LHON mutations introduced into neuronal NT2 cells. | Wong A | Human molecular genetics | 2002 | PMID: 11854175 |
Functional analysis of lymphoblast and cybrid mitochondria containing the 3460, 11778, or 14484 Leber's hereditary optic neuropathy mitochondrial DNA mutation. | Brown MD | The Journal of biological chemistry | 2000 | PMID: 10976107 |
Central nervous system involvement in Leber's optic neuropathy. | Paulus W | Journal of neurology | 1993 | PMID: 8496715 |
Molecular genetic analysis of a sporadic case of Leber hereditary optic neuropathy. | Howell N | American journal of human genetics | 1992 | PMID: 1734726 |
Mitochondrial DNA complex I and III mutations associated with Leber's hereditary optic neuropathy. | Brown MD | Genetics | 1992 | PMID: 1732158 |
Mitochondrial ND-I mutation in Leber hereditary optic neuropathy. | Johns DR | American journal of human genetics | 1992 | PMID: 1550131 |
Electron transfer properties of NADH:ubiquinone reductase in the ND1/3460 and the ND4/11778 mutations of the Leber hereditary optic neuroretinopathy (LHON). | Majander A | FEBS letters | 1991 | PMID: 1959619 |
Leber hereditary optic neuropathy: identification of the same mitochondrial ND1 mutation in six pedigrees. | Howell N | American journal of human genetics | 1991 | PMID: 1928099 |
Alternative, simultaneous complex I mitochondrial DNA mutations in Leber's hereditary optic neuropathy. | Johns DR | Biochemical and biophysical research communications | 1991 | PMID: 1900003 |
A new mtDNA mutation associated with Leber hereditary optic neuroretinopathy. | Huoponen K | American journal of human genetics | 1991 | PMID: 1674640 |
[Laparoscopy in the diagnosis of hepatic tumours (author's transl)]. | Charousek J | Ceskoslovenska gastroenterologie a vyziva | 1975 | PMID: 173472 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/56afc669-34e6-4f09-9065-ca12c73f2299 | - | - | - | - |
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Text-mined citations for rs199476118 ...
HelpRecord last updated May 19, 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.