ClinVar Genomic variation as it relates to human health
m.4295A>G
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.
Uncertain significance(3); Benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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m.4295A>G
Variation ID: 9603 Accession: VCV000009603.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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MT: 4295 (GRCh38) [ NCBI UCSC ] MT: 4295 (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 Jan 19, 2020 Jul 12, 2019 - HGVS
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Nucleotide Protein Molecular
consequenceNC_012920.1:m.4295A>G - Protein change
- Other names
- 4295A-G
- Canonical SPDI
- NC_012920.1:4294:A:G
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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-TI | - | - | GRCh38 | 26 | 27 |
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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Apr 1, 2012 | RCV000010226.2 | |
Pathogenic (1) |
no assertion criteria provided
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Apr 1, 2012 | RCV000022900.2 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Mar 22, 2019 | RCV000224071.10 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV000223744.1 | |
Benign (1) |
criteria provided, single submitter
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Jul 12, 2019 | RCV000850718.1 |
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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Uncertain significance
(Dec 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: SCV000884154.1
First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016 |
Comment:
The m.4295A>G variant (rs121434467) is located at position 33 of the tRNA-isoleucine gene. Although this variant has been reported in patients with diverse symptoms including … (more)
The m.4295A>G variant (rs121434467) is located at position 33 of the tRNA-isoleucine gene. Although this variant has been reported in patients with diverse symptoms including hypertrophic cardiomyopathy, encephalopathy, non-syndromic hearing loss, occipital stroke and essential hypertension, a consistent clinical presentation has not been identified (Finnila 2001, Gutierrez Cortes 2012, Li 2008, Merante 1996, Zhu 2009). Functional characterization of the variant tRNA indicates a defect in 3' processing (Levinger 2003), resulting in reduced activity of complex III in oxidative phosphorylation; however, the clinical relevance of these observations in not known (Gutierrez Cortes 2012, Merante 1996). Furthermore, the m.4295A>G variant is observed in 10 percent of individuals with the mitochondrial haplogroup K1a (87 out of 916 individual in the MITOMAP database). Therefore, based on the available information, the clinical significance of the m.4295A>G variant cannot be determined with certainty. (less)
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Benign
(Jul 12, 2019)
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criteria provided, single submitter
Method: clinical testing
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Juvenile myopathy, encephalopathy, lactic acidosis AND stroke
Affected status: unknown
Allele origin:
germline
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Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine
Accession: SCV000992951.1
First in ClinVar: Sep 22, 2019 Last updated: Sep 22, 2019 |
Comment:
The NC_012920.1:m.4295A>G variant in MT-TI gene is interpreted to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following … (more)
The NC_012920.1:m.4295A>G variant in MT-TI gene is interpreted to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: BS1, BS4 (less)
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Uncertain significance
(Mar 22, 2019)
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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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Athena Diagnostics Inc
Accession: SCV001144615.1
First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2020 |
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Uncertain Significance
(Jan 19, 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: SCV000281548.1
First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016 |
Comment:
Converted during submission to Uncertain significance.
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Pathogenic
(Apr 01, 2012)
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no assertion criteria provided
Method: literature only
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DEAFNESS, NONSYNDROMIC SENSORINEURAL, MITOCHONDRIAL
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000044191.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
Merante et al. (1996) identified a 4295A-G transition in the MTTI gene in a 7-month-old girl who had had sudden onset of cyanotic spells and … (more)
Merante et al. (1996) identified a 4295A-G transition in the MTTI gene in a 7-month-old girl who had had sudden onset of cyanotic spells and died as a result of complications of hypertrophic cardiomyopathy (see 192600). Despite the hypertrophied left ventricle demonstrated by autopsy, the patient had had no symptoms of cardiac failure, exercise intolerance, or cyanosis until shortly before admission to the hospital, and normal developmental milestones had been achieved. Ultrastructural studies of tissue at autopsy showed massive proliferation of mitochondria in heart and liver but not in skeletal muscle fibers. A brother was found to have concentric left ventricular hypertrophic cardiomyopathy, mild mitral regurgitation, and an ejection fraction of 47% at 2 years of age. Neurologic examination at age 5 was normal, but endocardial biopsy showed mitochondrial hypertrophy. The brother subsequently underwent cardiac transplantation after a sudden deterioration of cardiac function and was 'doing well' 8 months after transplant. Two additional children, aged 6 and 2, demonstrated no cardiac symptoms, but an abnormally elevated blood lactate level was found in one. Again extensive neurologic examinations were normal. The mother, 32 years of age at the time of report, was asymptomatic and her endocardial biopsy showed no mitochondrial hypertrophy. The 4295A-G transition was heteroplasmic in this case. The mutant mitochondrial chromosome was present in approximately 90% in the heart tissue of the proband and the affected brother; the mother had less mutant DNA (approximately 78%), well below the expected expression threshold for the disease. In the proband and other members of the family, the proportion of mutant DNA in different tissues varied widely due to replicative segregation. In affected members of a 3-generation family with maternally inherited nonsyndromic sensorineural deafness (500008), Gutierrez Cortes et al. (2012) identified a homoplasmic 4295A-G transition in the MTTI gene. Cybrid cell lines carrying the mutation showed a 50% decline in mitochondrial oxygen consumption and a decrease of 37% in complex III activity compared to controls, indicating a defect in mitochondrial respiration. Complex III assembly, as assessed by gel electrophoresis, was also decreased (32% compared to controls), while other complexes were normal. Reduced penetrance was observed. (less)
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Pathogenic
(Apr 01, 2012)
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no assertion criteria provided
Method: literature only
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CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000030450.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
Merante et al. (1996) identified a 4295A-G transition in the MTTI gene in a 7-month-old girl who had had sudden onset of cyanotic spells and … (more)
Merante et al. (1996) identified a 4295A-G transition in the MTTI gene in a 7-month-old girl who had had sudden onset of cyanotic spells and died as a result of complications of hypertrophic cardiomyopathy (see 192600). Despite the hypertrophied left ventricle demonstrated by autopsy, the patient had had no symptoms of cardiac failure, exercise intolerance, or cyanosis until shortly before admission to the hospital, and normal developmental milestones had been achieved. Ultrastructural studies of tissue at autopsy showed massive proliferation of mitochondria in heart and liver but not in skeletal muscle fibers. A brother was found to have concentric left ventricular hypertrophic cardiomyopathy, mild mitral regurgitation, and an ejection fraction of 47% at 2 years of age. Neurologic examination at age 5 was normal, but endocardial biopsy showed mitochondrial hypertrophy. The brother subsequently underwent cardiac transplantation after a sudden deterioration of cardiac function and was 'doing well' 8 months after transplant. Two additional children, aged 6 and 2, demonstrated no cardiac symptoms, but an abnormally elevated blood lactate level was found in one. Again extensive neurologic examinations were normal. The mother, 32 years of age at the time of report, was asymptomatic and her endocardial biopsy showed no mitochondrial hypertrophy. The 4295A-G transition was heteroplasmic in this case. The mutant mitochondrial chromosome was present in approximately 90% in the heart tissue of the proband and the affected brother; the mother had less mutant DNA (approximately 78%), well below the expected expression threshold for the disease. In the proband and other members of the family, the proportion of mutant DNA in different tissues varied widely due to replicative segregation. In affected members of a 3-generation family with maternally inherited nonsyndromic sensorineural deafness (500008), Gutierrez Cortes et al. (2012) identified a homoplasmic 4295A-G transition in the MTTI gene. Cybrid cell lines carrying the mutation showed a 50% decline in mitochondrial oxygen consumption and a decrease of 37% in complex III activity compared to controls, indicating a defect in mitochondrial respiration. Complex III assembly, as assessed by gel electrophoresis, was also decreased (32% compared to controls), while other complexes were normal. Reduced penetrance was observed. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280195.1
First in ClinVar: Jun 01, 2016 Last updated: Jun 01, 2016 |
Comment:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case … (more)
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MTTI m.4295A>G Merante et al (1996) report the variant in two siblings with severe HCM and their mother who was phenotype negative. The proband presented at 7 months of age with cyanosis and died due to complications of HCM. Autopsy revealed proliferation of mitochondria in the heart, so the authors looked for mitochondrial variants. Notably, they did only a limited analysis of mitochondrial DNA; they sequenced tRNA genes and looked for gross deletions and duplications. The proband, who had the most severe presentation, had a >90 % heteroplasmic load in the heart, her brother had 89% variant load in the heart and developed HCM at age 4 while their mother who had a variant load of 79% in the cardiac muscle was phenotype negative for HCM but did have reduced respiratory chain activity levels. Adenosine is highly conserved at position 4295 across species. This variant has been reported in individuals from the general population: 5/2704 individuals in mtDB (www.genpath.uu.se/mtDB); 2/3735 individuals in MitoWheel (http://mitowheel.org/mitowheel.html ). (less)
Number of individuals with the variant: 4
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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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Interpretation of mitochondrial tRNA variants. | Wong LC | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 31965079 |
Novel mitochondrial DNA mutations responsible for maternally inherited nonsyndromic hearing loss. | Gutiérrez Cortés N | Human mutation | 2012 | PMID: 22241583 |
Maternally inherited hypertension is associated with the mitochondrial tRNA(Ile) A4295G mutation in a Chinese family. | Li Z | Biochemical and biophysical research communications | 2008 | PMID: 18177739 |
Mitochondrial genome mutations in hypertensive individuals. | Schwartz F | American journal of hypertension | 2004 | PMID: 15233983 |
Pathology-related substitutions in human mitochondrial tRNA(Ile) reduce precursor 3' end processing efficiency in vitro. | Levinger L | Nucleic acids research | 2003 | PMID: 12655007 |
Phylogenetic analysis of mitochondrial DNA in patients with an occipital stroke. Evaluation of mutations by using sequence data on the entire coding region. | Finnilä S | Mutation research | 2001 | PMID: 11406419 |
Automating the identification of DNA variations using quality-based fluorescence re-sequencing: analysis of the human mitochondrial genome. | Rieder MJ | Nucleic acids research | 1998 | PMID: 9461455 |
An additional mitochondrial tRNA(Ile) point mutation (A-to-G at nucleotide 4295) causing hypertrophic cardiomyopathy. | Merante F | Human mutation | 1996 | PMID: 8889580 |
Text-mined citations for rs121434467 ...
HelpRecord last updated Mar 11, 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.