ClinVar Genomic variation as it relates to human health
m.10197G>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.10197G>A
Variation ID: 9715 Accession: VCV000009715.39
- Type and length
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single nucleotide variant, 1 bp
- Location
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MT: 10197 (GRCh38) [ NCBI UCSC ] MT: 10197 (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 Jun 17, 2023 Jul 25, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNC_012920.1:m.10197G>A - Protein change
- Other names
- MTND3, 10197G-A, ALA47THR
- A47T
- Canonical SPDI
- NC_012920.1:10196: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
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
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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-ND3 | - | - | GRCh38 | 44 | 59 |
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
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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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Oct 1, 2009 | RCV000010363.5 | |
Pathogenic (1) |
no assertion criteria provided
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Oct 1, 2009 | RCV000010362.3 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 17, 2019 | RCV000144011.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 29, 2017 | RCV000507278.9 | |
Pathogenic (1) |
criteria provided, single submitter
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May 4, 2022 | RCV002247309.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 22, 2022 | RCV002285008.1 | |
Pathogenic (1) |
reviewed by expert panel
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Jul 25, 2022 | RCV002291213.1 |
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
(Jul 25, 2022)
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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: SCV002583527.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Comment:
The m.10197G>A (p.A47T) variant in MT-ND3 has been reported in at least 22 probands with primary mitochondrial disease. Affected individuals had variable ages of onset … (more)
The m.10197G>A (p.A47T) variant in MT-ND3 has been reported in at least 22 probands with primary mitochondrial disease. Affected individuals had variable ages of onset (first months of life to childhood to adulthood). Features included Leigh syndrome, Leigh syndrome/MELAS overlap, and LHON with good visual recovery. Heteroplasmy levels were variable among tissues and affected individuals, and ranged from 10% (in an individual with LHON) to homoplasmy (in an individual with Leigh syndrome; PS4; PMIDs: 15372108, 17152068, 17413873, 18977334, 19458970, 20818383, 20972245, 24708134, 30128709, 30199507, 30776730, 32045392; two articles with no PMIDs: Pereira et al., 2019; JIEMS, 2019, Vol7: e20180003; Huang et al., 2017, J Clin Exp Ophthalmol 2017, 8:4). 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: 17152068, 17413873, 30128709, 30776730). This variant occurred de novo in at least three individuals (PM6_moderate, PMIDs: 24708134, 17413873; article with no PMID: Huang et al., 2017, J Clin Exp Ophthalmol 2017, 8:4). There are four occurrences of this variant in the GenBank dataset, and three of these four are not listed as patient sequences. However, upon discussion on the Expert Panel (EP) call, concern was raised that phylogenetic studies use patient samples and submit these to GenBank. This variant is absent in gnomAD v3.1.2 and in Helix dataset so the EP agreed to consider this supporting line of evidence (PM2_supporting). Cybrid studies showed a correlation between higher heteroplasmy level and lower complex I activity (PS3_supporting, PMID: 17152068). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.88 (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/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on July 25, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3, PP1_moderate, PS3_supporting, PM6_moderate, PS4. (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: SCV000997669.1
First in ClinVar: Nov 02, 2019 Last updated: Nov 02, 2019 |
Comment:
The NC_012920.1:m.10197G>A (YP_003024033.1:p.Ala47Thr) variant in MTND3 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.10197G>A (YP_003024033.1:p.Ala47Thr) variant in MTND3 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
(Sep 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
(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: SCV002574884.1
First in ClinVar: Sep 24, 2022 Last updated: Sep 24, 2022 |
Clinical Features:
Nephrocalcinosis (present) , Gait ataxia (present) , Basal ganglia calcification (present) , Increased CSF lactate (present)
Sex: female
Tissue: Blood
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Pathogenic
(Sep 29, 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: SCV000604295.2
First in ClinVar: Sep 30, 2017 Last updated: Feb 17, 2019 |
Comment:
The m.10197G>A variant (rs267606891) affects the MT-ND3 gene involved in mitochondrial complex I (CI) function, and has been identified in several patients with symptoms of … (more)
The m.10197G>A variant (rs267606891) affects the MT-ND3 gene involved in mitochondrial complex I (CI) function, and has been identified in several patients with symptoms of Leigh disease (LD), LD-like, dystonia, and/or other symptoms associated with CI dysfunction (see link to GeneReviews below). This variant was first identified by Kirby (2004), wherein a patient harboring this variant is described as having LD-like symptoms and was shown to have reduced CI activity in cultured fibroblasts. Subsequent studies have also identified this variant in a French family affected with LS (Sarzi 2007), a Korean family with basal ganglia lesions (Chae 2007), and a single individual with LS (Valente 2009). All affected individuals studied have also been shown to have reduced CI activity in cell culture. Also, when analyzed, the degree of heteroplasmy tracks with disease severity, with asymptomatic carriers showing reduced levels of variant load compared to affected patients. Additionally, this variant is rare in MITOMAP, and is not associated with any particular haplogroup. Therefore, the m.10197G>A variant satisfies our criteria for classification as pathogenic. (less)
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Pathogenic
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial DNA-Associated Leigh Syndrome and NARP
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002517670.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Leigh syndrome
Affected status: yes
Allele origin:
de novo
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Pediatric Department, Xiangya Hospital, Central South University
Accession: SCV002761209.1
First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023 |
Clinical Features:
Seizure (present) , Developmental regression (present) , Abnormal basal ganglia MRI signal intensity (present) , Abnormal brainstem MRI signal intensity (present)
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Pathogenic
(Oct 01, 2009)
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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: SCV000030589.2
First in ClinVar: Apr 04, 2013 Last updated: Dec 16, 2018 |
Comment on evidence:
In affected members of 3 unrelated families with Leigh syndrome (see 256000) or dystonia, Sarzi et al. (2007) identified a 10197G-A transition in the MTND3 … (more)
In affected members of 3 unrelated families with Leigh syndrome (see 256000) or dystonia, Sarzi et al. (2007) identified a 10197G-A transition in the MTND3 gene, resulting in an ala47-to-thr (A47T) substitution in a highly conserved part of the ND3 subunit. The mutation was found to be homoplasmic in the most severely affected patients (children), whereas the mutant load varied from 50% in the leukocytes of a healthy mother to 67% and 74%, respectively, in the 2 mildly affected mothers. Sarzi et al. (2007) concluded that 10197G-A is a common mtDNA mutation responsible for Leigh syndrome and dystonia. Chae et al. (2007) identified the 10197G-A mutation in 3 Korean patients with Leigh syndrome due to complex I deficiency (500014). Two sibs had childhood-onset progressive generalized dystonia, whereas the third unrelated child had stroke-like episodes in infancy. All 3 had bilateral lesions in the basal ganglia. Muscle biopsies showed 98%, 86%, and 80% heteroplasmy, respectively, for the mutation. Wang et al. (2009) identified a homoplasmic 10197G-A mutation in 6 affected members of a Chinese Han family with Leber optic atrophy and dystonia (500001). The mutation occurred on mitochondrial haplogroup D4b. The proband, who was most severely affected, developed an abnormal gait at age 5 years after a bout of diarrhea. At age 14 years, he had painless and progressive visual loss, and lost ambulation due to dystonia. There was no evidence of mental or psychomotor retardation. By the third decade, he was unable to stand or speak clearly. Neurologic exam showed generalized spastic dystonia involving the limbs, trunk, neck, and face, with diffuse muscle wasting. Brain MRI showed abnormal signals in the basal ganglia. Other family members had a similar, but less severe, disease course with spastic gait, dystonia, visual loss, and basal ganglia lesions. Nine additional family members with a homoplasmic mutation had sudden onset of painless vision loss due to optic atrophy between ages 14 and 30 years, but without other symptoms. A tenth patient had loss of vision and was found to have postural tremor, hyperreflexia, and unstable gait. Two unaffected family members also carried the homoplasmic mutation, suggesting incomplete penetrance. (less)
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Pathogenic
(Oct 01, 2009)
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no assertion criteria provided
Method: literature only
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MITOCHONDRIAL COMPLEX I DEFICIENCY, MITOCHONDRIAL TYPE 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000030588.2
First in ClinVar: Apr 04, 2013 Last updated: Dec 16, 2018 |
Comment on evidence:
In affected members of 3 unrelated families with Leigh syndrome (see 256000) or dystonia, Sarzi et al. (2007) identified a 10197G-A transition in the MTND3 … (more)
In affected members of 3 unrelated families with Leigh syndrome (see 256000) or dystonia, Sarzi et al. (2007) identified a 10197G-A transition in the MTND3 gene, resulting in an ala47-to-thr (A47T) substitution in a highly conserved part of the ND3 subunit. The mutation was found to be homoplasmic in the most severely affected patients (children), whereas the mutant load varied from 50% in the leukocytes of a healthy mother to 67% and 74%, respectively, in the 2 mildly affected mothers. Sarzi et al. (2007) concluded that 10197G-A is a common mtDNA mutation responsible for Leigh syndrome and dystonia. Chae et al. (2007) identified the 10197G-A mutation in 3 Korean patients with Leigh syndrome due to complex I deficiency (500014). Two sibs had childhood-onset progressive generalized dystonia, whereas the third unrelated child had stroke-like episodes in infancy. All 3 had bilateral lesions in the basal ganglia. Muscle biopsies showed 98%, 86%, and 80% heteroplasmy, respectively, for the mutation. Wang et al. (2009) identified a homoplasmic 10197G-A mutation in 6 affected members of a Chinese Han family with Leber optic atrophy and dystonia (500001). The mutation occurred on mitochondrial haplogroup D4b. The proband, who was most severely affected, developed an abnormal gait at age 5 years after a bout of diarrhea. At age 14 years, he had painless and progressive visual loss, and lost ambulation due to dystonia. There was no evidence of mental or psychomotor retardation. By the third decade, he was unable to stand or speak clearly. Neurologic exam showed generalized spastic dystonia involving the limbs, trunk, neck, and face, with diffuse muscle wasting. Brain MRI showed abnormal signals in the basal ganglia. Other family members had a similar, but less severe, disease course with spastic gait, dystonia, visual loss, and basal ganglia lesions. Nine additional family members with a homoplasmic mutation had sudden onset of painless vision loss due to optic atrophy between ages 14 and 30 years, but without other symptoms. A tenth patient had loss of vision and was found to have postural tremor, hyperreflexia, and unstable gait. Two unaffected family members also carried the homoplasmic mutation, suggesting incomplete penetrance. (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: SCV000188903.5
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 |
Mitochondrial ND3 as the novel causative gene for Leber hereditary optic neuropathy and dystonia. | Wang K | Neurogenetics | 2009 | PMID: 19458970 |
A novel ND3 mitochondrial DNA mutation in three Korean children with basal ganglia lesions and complex I deficiency. | Chae JH | Pediatric research | 2007 | PMID: 17413873 |
A novel recurrent mitochondrial DNA mutation in ND3 gene is associated with isolated complex I deficiency causing Leigh syndrome and dystonia. | Sarzi E | American journal of medical genetics. Part A | 2007 | PMID: 17152068 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/c72f6ab6-c819-4a12-9d85-fe7e9d5cbc57 | - | - | - | - |
Text-mined citations for rs267606891 ...
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.