ClinVar Genomic variation as it relates to human health
m.13513G>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.13513G>A
Variation ID: 9702 Accession: VCV000009702.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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MT: 13513 (GRCh38) [ NCBI UCSC ] MT: 13513 (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 Mar 24, 2015 Oct 14, 2023 Oct 26, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNC_012920.1:m.13513G>A - Protein change
- Other names
- MTND5, 13513G-A, ASP393ASN
- D393N
- Canonical SPDI
- NC_012920.1:13512: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: CA120632
- Genetic Testing Registry (GTR): GTR000500597
- Genetic Testing Registry (GTR): GTR000556608
- Genetic Testing Registry (GTR): GTR000591967
- Genetic Testing Registry (GTR): GTR000591969
- Genetic Testing Registry (GTR): GTR000591975
- Genetic Testing Registry (GTR): GTR000591976
- OMIM: 516005.0007
- dbSNP: rs267606897
- 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
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. |
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MT-ND5 | - | - | GRCh38 | 307 | 324 |
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 (1) |
no assertion criteria provided
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Mar 1, 2008 | RCV000010346.4 | |
Pathogenic (2) |
no assertion criteria provided
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Mar 1, 2008 | RCV000010345.6 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Sep 22, 2022 | RCV000144016.8 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 23, 2020 | RCV000224472.3 | |
Pathogenic (3) |
reviewed by expert panel
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Oct 26, 2021 | RCV000494941.3 |
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
(Oct 26, 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: SCV002037590.1
First in ClinVar: Dec 23, 2021 Last updated: Dec 23, 2021 |
Comment:
The m.13513G>A (p. D393N) variant in MT-ND5 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant … (more)
The m.13513G>A (p. D393N) variant in MT-ND5 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 onset typically in childhood with some reports of onset in adolescence who had features variably consistent with Leigh syndrome, MELAS and MELAS-like, and/or mitochondrial encephalopathy (PS4; PMID: 25681084; PMID: 27344355; PMID: 30128709; PMID: 12624137; PMID: 14520659; PMID: 17400793; PMID: 18495510). This variant has been identified as a de novo occurrence in at least 5 probands with primary mitochondrial disease (PM6_strong; PMID: 27344355; PMID: 17400793; PMID: 18495510). This variant heteroplasmy level segregated with severity in 6 families where healthy mothers were found to have the variant at low heteroplasmy levels (PP1_moderate; PMID: 25681084; PMID: 12624137; PMID: 14520659). Another variant at this amino acid position leading to a different amino acid change is classified as pathogenic by mitomap.org and ClinVar – m.13514A>G (p.D393G; PM5). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.97 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). 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 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4, PM6_strong, PM5, PP1_moderate, PP3). (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: SCV000997986.1
First in ClinVar: Nov 02, 2019 Last updated: Nov 02, 2019 |
Comment:
The NC_012920.1:m.13513G>A (YP_003024036.1:p.Asp393Asn) variant in MTND5 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.13513G>A (YP_003024036.1:p.Asp393Asn) variant in MTND5 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
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446569.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Ptosis (present) , Abnormal corpus striatum morphology (present) , Abnormality of mitochondrial metabolism (present) , Increased CSF lactate (present)
Sex: female
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Pathogenic
(Sep 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Leigh syndrome
(Mitochondrial inheritance)
Affected status: yes
Allele origin:
germline
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Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin
Additional submitter:
CUBI - Core Unit Bioinformatics, Berlin Institute of Health
Accession: SCV002574885.1
First in ClinVar: Sep 24, 2022 Last updated: Sep 24, 2022 |
Clinical Features:
Hypospadias (present) , Brachycephaly (present) , Abnormal corpus callosum morphology (present) , Abnormal heart morphology (present) , Cardiomyopathy (present) , Global brain atrophy (present) , … (more)
Hypospadias (present) , Brachycephaly (present) , Abnormal corpus callosum morphology (present) , Abnormal heart morphology (present) , Cardiomyopathy (present) , Global brain atrophy (present) , Lactic acidosis (present) (less)
Sex: male
Tissue: Blood
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Pathogenic
(Oct 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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Leigh syndrome
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002580352.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Number of individuals with the variant: 4
Sex: male
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Pathogenic
(Jul 28, 2015)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000281330.1
First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016 |
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Pathogenic
(Aug 04, 2021)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial disease
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001949987.1
First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
Comment:
This variant was identified as heteroplasmic (40%)
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Pathogenic
(May 22, 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: SCV000577892.1
First in ClinVar: Jul 17, 2017 Last updated: Jul 17, 2017 |
Number of individuals with the variant: 1
Sex: male
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Pathogenic
(Mar 01, 2008)
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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: SCV000030572.2
First in ClinVar: Apr 04, 2013 Last updated: Feb 13, 2018 |
Comment on evidence:
In a patient with MELAS syndrome (540000), Santorelli et al. (1997) identified a heteroplasmic 13513G-A transition in the MTND5 gene, resulting in an asp393-to-asn (D393N) … (more)
In a patient with MELAS syndrome (540000), Santorelli et al. (1997) identified a heteroplasmic 13513G-A transition in the MTND5 gene, resulting in an asp393-to-asn (D393N) substitution. Kirby et al. (2003) identified the D393N mutation in 3 unrelated patients with Leigh syndrome (256000) and complex I deficiency (252010). The mutation was present in mutant loads of approximately 50% or less in all tissues tested, including multiple brain regions. The threshold mutant load for causing a complex I defect in cultured cells was approximately 30%. The findings suggested that the mutation causes a complex I defect when present at unusually low mutant loads and may act dominantly. In 3 of 14 unrelated children with Leigh syndrome and complex I deficiency, Chol et al. (2003) identified the D393N mutation in the MTND5 gene. All 3 children had a peculiar MRI aspect distinct from typical Leigh syndrome: brain MRI consistently showed a specific involvement of the substantia nigra and medulla oblongata sparing the basal ganglia. The mutation, which affects an evolutionarily conserved amino acid, had previously been observed in adult patients with MELAS syndrome or an overlap of Leber hereditary optic neuropathy (LHON; 535000) and MELAS syndromes (Pulkes et al., 1999), emphasizing the clinical heterogeneity of mitochondrial DNA mutations. Sudo et al. (2004) identified the D393N mutation in 6 of 84 (7%) Japanese patients with Leigh syndrome. The proportions of mutant mtDNA in muscles were relatively low (42 to 70%). The onset in patients with this mutation was delayed compared to those with the more common mutations at nucleotide 8993 in the MTATP6 gene (see 516060.0001 and 516060.0002), and ptosis and cardiac conduction abnormalities were frequently seen (83%). Sudo et al. (2004) suggested that the 13513G-A mutation is a frequent cause of Leigh syndrome and that patients with this mutation may have a characteristic clinical course. In a clinical presentation case, Dickerson et al. (2005) discussed a patient with the MELAS syndrome due to the 13513G-A mutation who had onset of her illness in her early sixties, making her the oldest patient with this syndrome known to carry that specific mutation. The onset of the clinical manifestations consisted of seizures and altered mental status at the age of 61 years. Difficulty hearing began about 6 months later. The patient died about 2 years after onset. Dickerson et al. (2005) stated that among the 6 reported patients with the MELAS syndrome and the 13513G-A mutation, all had the clinical features of the disorder, including hearing loss, by their mid-forties, and most were in their second decade at onset. Blok et al. (2007) reported 2 unrelated patients with oxidative phosphorylation defects associated with low levels of 13513G-A heteroplasmy. An 11-year-old girl presented with exercise intolerance and mild developmental delay. Brain MRI showed a subinsular cerebral infarct consistent with MELAS. She also had mild external ophthalmoplegia and strabismus. Skeletal muscle biopsy as an adult showed decreased complex I activity (58% of control). The mutation was present in blood (4 to 6%), fibroblasts (1 to 5%) and muscle (13 to 15%). A 5-month-old boy with a MELAS/Leigh phenotype showed failure to thrive, psychomotor retardation, retinitis pigmentosa, microcytic anemia, and characteristic brain lesions on MRI. He died at age 19 months after a viral infection. Skeletal muscle complex I activity was 8% of control; the mutation was present at 11 to 17% in blood, hair, and skeletal muscle. Blok et al. (2007) noted that low loads of MTND5 mutations can still result in a severe clinical phenotype because ND5 synthesis is probably the rate-limiting step for the activity of complex I. Shanske et al. (2008) reported 12 patients with the 13513G-A mutation. The 3 adult patients had typical features of MELAS, whereas the other 9 infants and children had typical features of Leigh syndrome. Biochemical studies showed that complex I deficiency was inconsistent and generally mild, but mutation load in muscle and blood was relatively high. (less)
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Pathogenic
(Mar 01, 2008)
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no assertion criteria provided
Method: literature only
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MELAS SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000030571.2
First in ClinVar: Apr 04, 2013 Last updated: Feb 13, 2018 |
Comment on evidence:
In a patient with MELAS syndrome (540000), Santorelli et al. (1997) identified a heteroplasmic 13513G-A transition in the MTND5 gene, resulting in an asp393-to-asn (D393N) … (more)
In a patient with MELAS syndrome (540000), Santorelli et al. (1997) identified a heteroplasmic 13513G-A transition in the MTND5 gene, resulting in an asp393-to-asn (D393N) substitution. Kirby et al. (2003) identified the D393N mutation in 3 unrelated patients with Leigh syndrome (256000) and complex I deficiency (252010). The mutation was present in mutant loads of approximately 50% or less in all tissues tested, including multiple brain regions. The threshold mutant load for causing a complex I defect in cultured cells was approximately 30%. The findings suggested that the mutation causes a complex I defect when present at unusually low mutant loads and may act dominantly. In 3 of 14 unrelated children with Leigh syndrome and complex I deficiency, Chol et al. (2003) identified the D393N mutation in the MTND5 gene. All 3 children had a peculiar MRI aspect distinct from typical Leigh syndrome: brain MRI consistently showed a specific involvement of the substantia nigra and medulla oblongata sparing the basal ganglia. The mutation, which affects an evolutionarily conserved amino acid, had previously been observed in adult patients with MELAS syndrome or an overlap of Leber hereditary optic neuropathy (LHON; 535000) and MELAS syndromes (Pulkes et al., 1999), emphasizing the clinical heterogeneity of mitochondrial DNA mutations. Sudo et al. (2004) identified the D393N mutation in 6 of 84 (7%) Japanese patients with Leigh syndrome. The proportions of mutant mtDNA in muscles were relatively low (42 to 70%). The onset in patients with this mutation was delayed compared to those with the more common mutations at nucleotide 8993 in the MTATP6 gene (see 516060.0001 and 516060.0002), and ptosis and cardiac conduction abnormalities were frequently seen (83%). Sudo et al. (2004) suggested that the 13513G-A mutation is a frequent cause of Leigh syndrome and that patients with this mutation may have a characteristic clinical course. In a clinical presentation case, Dickerson et al. (2005) discussed a patient with the MELAS syndrome due to the 13513G-A mutation who had onset of her illness in her early sixties, making her the oldest patient with this syndrome known to carry that specific mutation. The onset of the clinical manifestations consisted of seizures and altered mental status at the age of 61 years. Difficulty hearing began about 6 months later. The patient died about 2 years after onset. Dickerson et al. (2005) stated that among the 6 reported patients with the MELAS syndrome and the 13513G-A mutation, all had the clinical features of the disorder, including hearing loss, by their mid-forties, and most were in their second decade at onset. Blok et al. (2007) reported 2 unrelated patients with oxidative phosphorylation defects associated with low levels of 13513G-A heteroplasmy. An 11-year-old girl presented with exercise intolerance and mild developmental delay. Brain MRI showed a subinsular cerebral infarct consistent with MELAS. She also had mild external ophthalmoplegia and strabismus. Skeletal muscle biopsy as an adult showed decreased complex I activity (58% of control). The mutation was present in blood (4 to 6%), fibroblasts (1 to 5%) and muscle (13 to 15%). A 5-month-old boy with a MELAS/Leigh phenotype showed failure to thrive, psychomotor retardation, retinitis pigmentosa, microcytic anemia, and characteristic brain lesions on MRI. He died at age 19 months after a viral infection. Skeletal muscle complex I activity was 8% of control; the mutation was present at 11 to 17% in blood, hair, and skeletal muscle. Blok et al. (2007) noted that low loads of MTND5 mutations can still result in a severe clinical phenotype because ND5 synthesis is probably the rate-limiting step for the activity of complex I. Shanske et al. (2008) reported 12 patients with the 13513G-A mutation. The 3 adult patients had typical features of MELAS, whereas the other 9 infants and children had typical features of Leigh syndrome. Biochemical studies showed that complex I deficiency was inconsistent and generally mild, but mutation load in muscle and blood was relatively high. (less)
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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: SCV000188908.5
First in ClinVar: Sep 09, 2014 Last updated: Oct 01, 2022 |
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not provided
(-)
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no classification provided
Method: literature only
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Juvenile myopathy, encephalopathy, lactic acidosis AND stroke
Affected status: unknown
Allele origin:
maternal
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GeneReviews
Accession: SCV004042635.1
First in ClinVar: Oct 14, 2023 Last updated: Oct 14, 2023 |
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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 |
MELAS. | Adam MP | - | 2018 | PMID: 20301411 |
The G13513A mutation in the ND5 gene of mitochondrial DNA as a common cause of MELAS or Leigh syndrome: evidence from 12 cases. | Shanske S | Archives of neurology | 2008 | PMID: 18332249 |
Mutations in the ND5 subunit of complex I of the mitochondrial DNA are a frequent cause of oxidative phosphorylation disease. | Blok MJ | Journal of medical genetics | 2007 | PMID: 17400793 |
Case records of the Massachusetts General Hospital. Case 36-2005. A 61-year-old woman with seizure, disturbed gait, and altered mental status. | Dickerson BC | The New England journal of medicine | 2005 | PMID: 16306525 |
Leigh syndrome caused by mitochondrial DNA G13513A mutation: frequency and clinical features in Japan. | Sudo A | Journal of human genetics | 2004 | PMID: 14730434 |
Low mutant load of mitochondrial DNA G13513A mutation can cause Leigh's disease. | Kirby DM | Annals of neurology | 2003 | PMID: 14520659 |
The mitochondrial DNA G13513A MELAS mutation in the NADH dehydrogenase 5 gene is a frequent cause of Leigh-like syndrome with isolated complex I deficiency. | Chol M | Journal of medical genetics | 2003 | PMID: 12624137 |
The mitochondrial DNA G13513A transition in ND5 is associated with a LHON/MELAS overlap syndrome and may be a frequent cause of MELAS. | Pulkes T | Annals of neurology | 1999 | PMID: 10589546 |
Identification of a novel mutation in the mtDNA ND5 gene associated with MELAS. | Santorelli FM | Biochemical and biophysical research communications | 1997 | PMID: 9299505 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/7dcf79c3-61e2-40bb-bb3a-06d45c7c2c23 | - | - | - | - |
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Text-mined citations for rs267606897 ...
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.