ClinVar Genomic variation as it relates to human health
m.14459G>A
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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m.14459G>A
Variation ID: 9689 Accession: VCV000009689.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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MT: 14459 (GRCh38) [ NCBI UCSC ] MT: 14459 (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 Apr 4, 2013 Oct 1, 2022 Nov 1, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNC_012920.1:m.14459G>A - Protein change
- Other names
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- Canonical SPDI
- NC_012920.1:14458: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
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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
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-ND6 | - | - | GRCh38 | 102 | 110 |
Conditions - Germline
Condition
Help
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
Help
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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Apr 15, 2006 | RCV000010326.2 | |
Pathogenic (1) |
no assertion criteria provided
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Apr 15, 2006 | RCV000010328.4 | |
Pathogenic (4) |
criteria provided, single submitter
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May 4, 2022 | RCV000010327.7 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Feb 11, 2021 | RCV000144019.8 | |
Pathogenic (1) |
reviewed by expert panel
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Nov 1, 2021 | RCV001796715.1 |
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
(Nov 01, 2021)
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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
Accession: SCV002037593.1
First in ClinVar: Dec 23, 2021 Last updated: Dec 23, 2021 |
Comment:
The m.14459G>A (p.A72V) variant in MT-ND6 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot … (more)
The m.14459G>A (p.A72V) variant in MT-ND6 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant has been reported in >16 individuals with primary mitochondrial disease with variable features ranging from Leber Hereditary Optic Neuropathy (LHON) with or without dystonia, Leigh syndrome, bilateral basal ganglia lesions, ataxia, and migraines (PS4; PMIDs: 8016139, 7654063, 16380132, 10894222, 14735584, 21749722, 14735585, 28503604, 32045392, 29408632, 22426787). This variant has been identified as a de novo occurrence in at least 2 probands with primary mitochondrial disease (PM6; PMIDs: 14735584, 10894222). This variant heteroplasmy level segregated with severity in six family members from four families (PP1_moderate; PMIDs: 22426787, 21749722, 7654063, 8016139). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.93 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Cybrid studies supported the functional impact of this variant including a deficiency seen in patient cell line that was transferred to cybrids with a high mutant load and study was reproducible (PS3_supporting; PMID: 8622678). 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 U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4, PM6, PP1_moderate, PP3, PS3_supporting. (less)
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Pathogenic
(Oct 17, 2019)
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criteria provided, single submitter
Method: clinical testing
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Leigh syndrome
Affected status: unknown
Allele origin:
germline
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Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine
Accession: SCV000998157.1
First in ClinVar: Nov 02, 2019 Last updated: Nov 02, 2019 |
Comment:
The NC_012920.1:m.14459G>A (YP_003024037.1:p.Ala72Val) variant in MTND6 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.14459G>A (YP_003024037.1:p.Ala72Val) variant in MTND6 gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PS1, PM9, PM10, PP4, PP6 (less)
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Pathogenic
(Feb 11, 2021)
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criteria provided, single submitter
Method: clinical testing
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Leigh syndrome
(Mitochondrial inheritance)
Affected status: yes
Allele origin:
maternal
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Breda Genetics srl
Accession: SCV001482520.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
Comment:
The variant m.14459G> A (p.Ala72Val) in the MT-ND6 gene is reported as pathogenic for Leigh syndrome and Leber hereditary optic neuropathy (LHON) in ClinVar (Variation … (more)
The variant m.14459G> A (p.Ala72Val) in the MT-ND6 gene is reported as pathogenic for Leigh syndrome and Leber hereditary optic neuropathy (LHON) in ClinVar (Variation ID: 9689) and is cited as pathogenic mutation in MITOMAP. The variant was identified in three out of 51836 sequences of the entire mitochondrial DNA (frequency 0.006%, GenBank, MITOMAP). This variant has previously been reported in patients with phenotypes ranging from Leigh or Leigh-like syndrome to Leber Hereditary Optic Neuropathy (LHON) plus dystonia, pure dystonia, pure LHON, or clinically asymptomatic. Jun et al. (1994) identified the variant m.14459G> A in heteroplasmy in a family with LHON and dystonia. Shoffner et al. (1995) identified the m.14459G> A mutation in a mother and daughter with isolated LHON (the daughter also had unilateral basal ganglia lesions on MRI). Kirby et al. (2000) identified the homoplasmic variant m.14459G> A in 3 patients with Leigh syndrome in whom there was no evidence of LHON or dystonia. Gropman and colleagues (2004) identified the m.14459G> A variant in a family with a broad spectrum of clinical manifestations. The proband presented with anarthria, dystonia, spasticity, and mild encephalopathy; MRI showed symmetrical and bilateral hyperintense lesions in the basal ganglia associated with cerebral and systemic lactic acidosis. Among other family members with the mutation, some were asymptomatic and others were symptomatic with varying clinical and laboratory characteristics, confirming the heterogeneous phenotype of this mutation even within the same family (OMIM * 516006). (less)
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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: SCV002517679.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Pathogenic
(Apr 15, 2006)
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no assertion criteria provided
Method: literature only
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LEBER OPTIC ATROPHY AND DYSTONIA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000030552.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In affected members of a large Hispanic family with Leber optic atrophy and dystonia (500001), Jun et al. (1994) identified a heteroplasmic 14459G-A transition in … (more)
In affected members of a large Hispanic family with Leber optic atrophy and dystonia (500001), Jun et al. (1994) identified a heteroplasmic 14459G-A transition in the MTND6 gene. This mutation results in an ala72-to-val (A72V) substitution. Leber optic atrophy predominated in the early generations and dystonia together with bilateral striatal necrosis was found in later generations. Among members of the later generations, 48% of the maternal relatives manifested dystonia, 10% LHON, and 3% LHON and dystonia. Shoffner et al. (1995) identified a heteroplasmic 14459G-A mutation in a mother and daughter with isolated LHON (535000) and in an unrelated girl with childhood-onset generalized dystonia. The daughter in the first family showed unilateral lesions in the basal ganglia on MRI, whereas the child in the second family had extensive bilateral lesions in the basal ganglia. Although the child with dystonia was severely affected, with dysarthria, quadriparesis, scoliosis, and pes cavus, intelligence was normal. The mother in the first family showed 50% heteroplasmy for the mutation in leukocytes, whereas her daughter showed homoplasmy in leukocytes and muscle. The girl in the second family showed 50% heteroplasmy for the mutation in skeletal muscle. In 3 patients with Leigh syndrome (256000) from 2 unrelated families, Kirby et al. (2000) identified the 14459G-A mutation in the MTND6 gene. There was no evidence of Leber optic atrophy or dystonia. Gropman et al. (2004) reported a family with a homoplasmic 14459G-A mtDNA mutation and a broad spectrum of clinical manifestations due to complex I deficiency (252010). The proband had anarthria, dystonia, spasticity, and mild encephalopathy, and an MRI revealed bilateral, symmetric basal ganglia lucencies associated with cerebral and systemic lactic acidosis. Among other family members with the mutation, some were asymptomatic and others were symptomatic with variable clinical and laboratory features, confirming the heterogeneous phenotype of homoplasmic 14459G-A mtDNA mutations, even within the same family. Watanabe et al. (2006) identified the 14459G-A mutation in 2 Japanese sisters with childhood-onset dystonia, mental deterioration, adult-onset LHON, and basal ganglia lesions. (less)
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Pathogenic
(Apr 15, 2006)
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no assertion criteria provided
Method: literature only
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LEIGH SYNDROME DUE TO MITOCHONDRIAL COMPLEX I DEFICIENCY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000030554.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In affected members of a large Hispanic family with Leber optic atrophy and dystonia (500001), Jun et al. (1994) identified a heteroplasmic 14459G-A transition in … (more)
In affected members of a large Hispanic family with Leber optic atrophy and dystonia (500001), Jun et al. (1994) identified a heteroplasmic 14459G-A transition in the MTND6 gene. This mutation results in an ala72-to-val (A72V) substitution. Leber optic atrophy predominated in the early generations and dystonia together with bilateral striatal necrosis was found in later generations. Among members of the later generations, 48% of the maternal relatives manifested dystonia, 10% LHON, and 3% LHON and dystonia. Shoffner et al. (1995) identified a heteroplasmic 14459G-A mutation in a mother and daughter with isolated LHON (535000) and in an unrelated girl with childhood-onset generalized dystonia. The daughter in the first family showed unilateral lesions in the basal ganglia on MRI, whereas the child in the second family had extensive bilateral lesions in the basal ganglia. Although the child with dystonia was severely affected, with dysarthria, quadriparesis, scoliosis, and pes cavus, intelligence was normal. The mother in the first family showed 50% heteroplasmy for the mutation in leukocytes, whereas her daughter showed homoplasmy in leukocytes and muscle. The girl in the second family showed 50% heteroplasmy for the mutation in skeletal muscle. In 3 patients with Leigh syndrome (256000) from 2 unrelated families, Kirby et al. (2000) identified the 14459G-A mutation in the MTND6 gene. There was no evidence of Leber optic atrophy or dystonia. Gropman et al. (2004) reported a family with a homoplasmic 14459G-A mtDNA mutation and a broad spectrum of clinical manifestations due to complex I deficiency (252010). The proband had anarthria, dystonia, spasticity, and mild encephalopathy, and an MRI revealed bilateral, symmetric basal ganglia lucencies associated with cerebral and systemic lactic acidosis. Among other family members with the mutation, some were asymptomatic and others were symptomatic with variable clinical and laboratory features, confirming the heterogeneous phenotype of homoplasmic 14459G-A mtDNA mutations, even within the same family. Watanabe et al. (2006) identified the 14459G-A mutation in 2 Japanese sisters with childhood-onset dystonia, mental deterioration, adult-onset LHON, and basal ganglia lesions. (less)
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Pathogenic
(Apr 15, 2006)
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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: SCV000030553.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In affected members of a large Hispanic family with Leber optic atrophy and dystonia (500001), Jun et al. (1994) identified a heteroplasmic 14459G-A transition in … (more)
In affected members of a large Hispanic family with Leber optic atrophy and dystonia (500001), Jun et al. (1994) identified a heteroplasmic 14459G-A transition in the MTND6 gene. This mutation results in an ala72-to-val (A72V) substitution. Leber optic atrophy predominated in the early generations and dystonia together with bilateral striatal necrosis was found in later generations. Among members of the later generations, 48% of the maternal relatives manifested dystonia, 10% LHON, and 3% LHON and dystonia. Shoffner et al. (1995) identified a heteroplasmic 14459G-A mutation in a mother and daughter with isolated LHON (535000) and in an unrelated girl with childhood-onset generalized dystonia. The daughter in the first family showed unilateral lesions in the basal ganglia on MRI, whereas the child in the second family had extensive bilateral lesions in the basal ganglia. Although the child with dystonia was severely affected, with dysarthria, quadriparesis, scoliosis, and pes cavus, intelligence was normal. The mother in the first family showed 50% heteroplasmy for the mutation in leukocytes, whereas her daughter showed homoplasmy in leukocytes and muscle. The girl in the second family showed 50% heteroplasmy for the mutation in skeletal muscle. In 3 patients with Leigh syndrome (256000) from 2 unrelated families, Kirby et al. (2000) identified the 14459G-A mutation in the MTND6 gene. There was no evidence of Leber optic atrophy or dystonia. Gropman et al. (2004) reported a family with a homoplasmic 14459G-A mtDNA mutation and a broad spectrum of clinical manifestations due to complex I deficiency (252010). The proband had anarthria, dystonia, spasticity, and mild encephalopathy, and an MRI revealed bilateral, symmetric basal ganglia lucencies associated with cerebral and systemic lactic acidosis. Among other family members with the mutation, some were asymptomatic and others were symptomatic with variable clinical and laboratory features, confirming the heterogeneous phenotype of homoplasmic 14459G-A mtDNA mutations, even within the same family. Watanabe et al. (2006) identified the 14459G-A mutation in 2 Japanese sisters with childhood-onset dystonia, mental deterioration, adult-onset LHON, and basal ganglia lesions. (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: SCV001760533.1
First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 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: SCV000086622.3
First in ClinVar: Oct 03, 2013 Last updated: Oct 01, 2022 |
Comment:
This mitochondrial DNA variant affects function. It hase been identified in at least two independent LHON pedigrees and segregates with affected disease status.
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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: SCV000188911.5
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 and NARP. | Adam MP | - | 2023 | PMID: 20301352 |
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 |
Leber's hereditary optic neuropathy with dystonia in a Japanese family. | Watanabe M | Journal of the neurological sciences | 2006 | PMID: 16380132 |
Variable clinical manifestation of homoplasmic G14459A mitochondrial DNA mutation. | Gropman A | American journal of medical genetics. Part A | 2004 | PMID: 14735585 |
Leigh disease caused by the mitochondrial DNA G14459A mutation in unrelated families. | Kirby DM | Annals of neurology | 2000 | PMID: 10894222 |
Use of transmitochondrial cybrids to assign a complex I defect to the mitochondrial DNA-encoded NADH dehydrogenase subunit 6 gene mutation at nucleotide pair 14459 that causes Leber hereditary optic neuropathy and dystonia. | Jun AS | Molecular and cellular biology | 1996 | PMID: 8622678 |
Leber's hereditary optic neuropathy plus dystonia is caused by a mitochondrial DNA point mutation. | Shoffner JM | Annals of neurology | 1995 | PMID: 7654063 |
A mitochondrial DNA mutation at nucleotide pair 14459 of the NADH dehydrogenase subunit 6 gene associated with maternally inherited Leber hereditary optic neuropathy and dystonia. | Jun AS | Proceedings of the National Academy of Sciences of the United States of America | 1994 | PMID: 8016139 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/a87cdf9b-c0e4-4872-9a99-be710c312acc | - | - | - | - |
Text-mined citations for rs199476105 ...
HelpRecord last updated Dec 09, 2023
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.