ClinVar Genomic variation as it relates to human health
NC_012920.1:m.8851T>C
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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NC_012920.1:m.8851T>C
Variation ID: 9645 Accession: VCV000009645.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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MT: 8851 (GRCh38) [ NCBI UCSC ] MT: 8851 (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 Apr 23, 2023 Mar 24, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNC_012920.1:m.8851T>C - Protein change
- Other names
- 8851T-C
- Canonical SPDI
- NC_012920.1:8850:T:C
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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
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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-ATP6 | - | - | GRCh38 | 265 | 310 |
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
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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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Sep 1, 2007 | RCV000010280.7 | |
Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jul 19, 2021 | RCV000144005.7 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 23, 2020 | RCV001268336.1 | |
Uncertain significance (2) |
criteria provided, single submitter
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Apr 21, 2023 | RCV001542705.4 | |
Uncertain significance (1) |
reviewed by expert panel
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Mar 24, 2022 | RCV002221472.1 |
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
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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
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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
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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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Uncertain significance
(Mar 24, 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: SCV002498784.1
First in ClinVar: Apr 16, 2022 Last updated: Apr 16, 2022 |
Comment:
The m.8851T>C (p.W109R) variant in MT-ATP6 has been reported in 4 individuals with features of primary mitochondrial disease from 3 families. Affected individuals had variable … (more)
The m.8851T>C (p.W109R) variant in MT-ATP6 has been reported in 4 individuals with features of primary mitochondrial disease from 3 families. Affected individuals had variable ages of onset (first months of life to 3 years old, one with onset in early 20s, one with onset in 50s). Several affected individuals had a period of normal development followed by delay and regression. Progressive neuromuscular involvement in later onset forms has also been seen. Features include developmental delay, microcephaly, choreoathetotic movements, ataxia, axonal neuropathy, progressive cognitive impairment, retinal dystrophy, hearing loss, and increase of subsarcolemmal mitochondria in muscle. Brain MRI showed bilateral basal ganglia lesions, Leigh syndrome, and cerebellar atrophy; and lab abnormalities included elevated blood and CSF lactate, and elevated ammonia with febrile viral infection. Heteroplasmy levels were generally variable, >68% in multiple tissues; one healthy mother had 85% heteroplasmy; and one healthy sib had 50-60% heteroplasmy (PS4_supporting; PMIDs: 8554662, 23206802, 33704825). There are no reports of de novo occurrence of this variant. 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; PMIDs: 8554662, 23206802). There are several occurrences of this variant in healthy population databases. Several studies in yeast (PMID: 31181185) support the functional impact of this variant and showed independent deleterious effects of the variant (PS3_moderate). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.69 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as uncertain significance 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 February 28, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS3_moderate, PS4_supporting, PP1, PP3. (less)
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Likely 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: SCV001447187.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Symmetric lesions of the basal ganglia (present) , Poor motor coordination (present) , Babinski sign (present) , Spastic paraplegia (present)
Sex: male
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Uncertain significance
(Apr 21, 2023)
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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: SCV002517646.2
First in ClinVar: May 28, 2022 Last updated: Apr 23, 2023 |
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Likely 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: SCV000997375.1
First in ClinVar: Nov 02, 2019 Last updated: Nov 02, 2019 |
Comment:
The NC_012920.1:m.8851T>C (YP_003024031.1:p.Trp109Arg) variant in MTATP6 gene is interpretated to be a Likely Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets … (more)
The NC_012920.1:m.8851T>C (YP_003024031.1:p.Trp109Arg) variant in MTATP6 gene is interpretated to be a Likely Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PM9, PM10, PP3, PP4, PP6 (less)
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Likely pathogenic
(Jul 19, 2021)
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criteria provided, single submitter
Method: clinical testing
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Leigh syndrome
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001950073.1
First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
Comment:
This variant was identified as homoplasmic
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Pathogenic
(Sep 01, 2007)
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no assertion criteria provided
Method: literature only
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BILATERAL STRIATAL NECROSIS, INFANTILE, MITOCHONDRIAL
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000030504.3
First in ClinVar: Apr 04, 2013 Last updated: Feb 01, 2019 |
Comment on evidence:
In a boy with bilateral striatal necrosis (500003), De Meirleir et al. (1995) identified an 8851T-C transition in the MTATP6 gene. The patient had less … (more)
In a boy with bilateral striatal necrosis (500003), De Meirleir et al. (1995) identified an 8851T-C transition in the MTATP6 gene. The patient had less than 3% normal mtDNA in fibroblasts and his unaffected mother had 15% normal mtDNA. The mtDNA of the grandmother had no trace of the mutation. (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: SCV001760536.1
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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Leigh syndrome
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000188892.5
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 |
The pathogenic MT-ATP6 m.8851T>C mutation prevents proton movements within the n-side hydrophilic cleft of the membrane domain of ATP synthase. | Kucharczyk R | Biochimica et biophysica acta. Bioenergetics | 2019 | PMID: 31181185 |
mtDNA lineage expansions in Sherpa population suggest adaptive evolution in Tibetan highlands. | Kang L | Molecular biology and evolution | 2013 | PMID: 24002810 |
Different laboratory and muscle biopsy findings in a family with an m.8851T>C mutation in the mitochondrial MTATP6 gene. | Honzik T | Molecular genetics and metabolism | 2013 | PMID: 23206802 |
Defining the pathogenesis of human mtDNA mutations using a yeast model: the case of T8851C. | Kucharczyk R | The international journal of biochemistry & cell biology | 2013 | PMID: 22789932 |
Long-term outcome of Leigh syndrome caused by the NARP-T8993C mtDNA mutation. | Debray FG | American journal of medical genetics. Part A | 2007 | PMID: 17663470 |
Bilateral striatal necrosis with a novel point mutation in the mitochondrial ATPase 6 gene. | De Meirleir L | Pediatric neurology | 1995 | PMID: 8554662 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/40d4031b-7f71-46c7-b0ec-dcbc5f538b7e | - | - | - | - |
Text-mined citations for rs199476136 ...
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.