ClinVar Genomic variation as it relates to human health
NC_012920.1:m.7444G>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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NC_012920.1:m.7444G>A
Variation ID: 9663 Accession: VCV000009663.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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MT: 7444 (GRCh38) [ NCBI UCSC ] MT: 7444 (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 Aug 5, 2023 Jun 26, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNC_012920.1:m.7444G>A - Protein change
- Other names
- MTCO1*LHON7444A
- *514K
- 7444G-A
- Canonical SPDI
- NC_012920.1:7443: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-CO1 | - | - | GRCh38 | 216 | - | |
MT-TS1 | - | - | GRCh38 | 29 | - |
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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Oct 1, 2005 | RCV000010299.4 | |
Pathogenic (2) |
no assertion criteria provided
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Oct 1, 2005 | RCV000010301.4 | |
Pathogenic (1) |
no assertion criteria provided
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Sep 14, 2007 | RCV000010300.4 | |
Benign (1) |
criteria provided, single submitter
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Oct 17, 2019 | RCV000854073.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 23, 2020 | RCV001268422.1 | |
Likely benign (1) |
reviewed by expert panel
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Jun 26, 2023 | RCV003319164.1 |
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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Likely benign
(Jun 26, 2023)
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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: SCV004023274.1
First in ClinVar: Aug 05, 2023 Last updated: Aug 05, 2023 |
Comment:
The m.7444G>A (p.term514K) in MT-CO1 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on June 26, 2023. This variant has … (more)
The m.7444G>A (p.term514K) in MT-CO1 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on June 26, 2023. This variant has been reported in several individuals with features of primary mitochondrial disease beginning in 1992 (Leber Hereditary Optic Neuropathy or LHON, PMID: 1322638; hearing loss, PMID: 16500624), however other genetic etiologies were not excluded due to technical limitations at the time and this variant is now recognized to be present at high frequencies in population databases. Furthermore, this variant has been seen in individuals with other well-known pathogenic mitochondrial DNA variants (family with LHON and m.3460G>A, PMID: 7901141; family with hearing loss and m.1555A>G, PMID: 16152638; BP2). The variant was seen at homoplasmy in affected and unaffected family members in several of these publications precluding consideration of segregation evidence. There are no reported de novo occurrences of this variant to our knowledge. Some functional characterization was performed in patient cells, however abnormalities noted were nonspecific and other genetic etiologies were not assessed (PMID: 1322638). This variant is present at considerable frequencies in population databases (BS1). The frequency in the MITOMAP GenBank sequences is 206/59,389 (0.347%; 12/12 individuals in Hg V7, 3/3 individuals in Hg H40b, 4/4 individuals in V7b, 4/4 individuals in W4b, 84/86 individuals in V7a, also seen in individuals from M22b, M38a, H11, HV20, P2, B2e, and others). The frequency in gnomAD v3.1.2 is 302/56,419 (0.535%). Indeed, there are 302 homoplasmic occurrences (seen in all populations except Amish and Middle Eastern, seen across every haplogroup listed; seen in individuals ages 30 years to >80 years) in addition to 10 heteroplasmic occurrences (seen in multiple populations, haplogroups, and heteroplasmy levels). The frequency in the Helix dataset is 775/195,983 (0.395%). Indeed, there are 775 homoplasmic occurrences (seen across many haplogroups) and 24 heteroplasmic occurrences (seen across many haplogroups). There are no in silico predictors for this type of variant in mitochondrial DNA. In summary, this variant meets criteria to be classified as likely benign for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on June 26, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied: BS1, BP2. (less)
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Benign
(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: SCV000997106.1
First in ClinVar: Nov 02, 2019 Last updated: Nov 02, 2019 |
Comment:
The NC_012920.1:m.7444G>A (YP_003024028.1:p.Ter514LysextX4) variant in MTCO1 gene is interpretated to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the … (more)
The NC_012920.1:m.7444G>A (YP_003024028.1:p.Ter514LysextX4) variant in MTCO1 gene is interpretated to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BS1, BS2 (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
(Mitochondrial inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447349.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Global developmental delay (present)
Sex: female
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Pathogenic
(Oct 01, 2005)
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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: SCV000030526.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
See 535000. This allele converts the AGA termination codon to a lysine codon (AAA), permitting extension of the MTCO1 polypeptide by 3 amino acids (lysine, … (more)
See 535000. This allele converts the AGA termination codon to a lysine codon (AAA), permitting extension of the MTCO1 polypeptide by 3 amino acids (lysine, glutamine, lysine) into the antisense tRNAser(UCN) sequence (Brown et al., 1992; Johns and Neufield, 1993). The mutation is associated with an impaired mobility of the polypeptide on SDS-PAGE and a 36% reduction in Complex IV activity in patient lymphoblasts. Patients with this mutation cluster within the Caucasian mtDNA phylogenetic tree (Brown et al., 1992). However, the 2 cases that have been extensively studied also harbor other LHON mutations: the MTND1*LHON3460A mutation in one case and the MTND6*LHON14484A in the other. Hence, the MTCO1*LHON7444A mutation is probably a secondary LHON mutation (Brown and Wallace, 1994). In the 2 families that harbored this mutation, between 23 and 43% of the maternal relatives were affected with all the affected individuals being male (Brown, Lott and Wallace, unpublished data). Pandya et al. (1999) reported 6 unrelated Mongolian deaf students with cosegregation of a 7444G-A mutation and a 1555A-G mutation in the MTRNR1 gene (561000.0001). Five of the individuals had a family history consistent with matrilineal transmission of hearing loss (500008). Only 2 individuals had a definite history of aminoglycoside exposure, but all 6 had severe to profound bilateral sensorineural hearing loss detected at birth or in infancy. Pandya et al. (1999) suggested that the 7444G-A mutation would share a common pathogenic mechanism as the adjacent 7445A-G mutation (590080.0002) in the MTTS1 gene, which results in aberrant processing of the tRNA-ser(UCN) precursor (see Guan et al., 1998). Yuan et al. (2005) reported cosegregation of a homoplasmic 7444G-A mutation and a homoplasmic 1555A-G MTRNR1 mutation in a 3-generation Chinese family with aminoglycoside-induced sensorineural hearing loss (580000). One additional family member with both mutations, who had a history of exposure to noise but not to aminoglycoside, exhibited mild hearing impairment. The dosage and age at the time of drug administration seemed to be correlated with the severity of the hearing loss. (less)
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Pathogenic
(Oct 01, 2005)
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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: SCV000030523.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
See 535000. This allele converts the AGA termination codon to a lysine codon (AAA), permitting extension of the MTCO1 polypeptide by 3 amino acids (lysine, … (more)
See 535000. This allele converts the AGA termination codon to a lysine codon (AAA), permitting extension of the MTCO1 polypeptide by 3 amino acids (lysine, glutamine, lysine) into the antisense tRNAser(UCN) sequence (Brown et al., 1992; Johns and Neufield, 1993). The mutation is associated with an impaired mobility of the polypeptide on SDS-PAGE and a 36% reduction in Complex IV activity in patient lymphoblasts. Patients with this mutation cluster within the Caucasian mtDNA phylogenetic tree (Brown et al., 1992). However, the 2 cases that have been extensively studied also harbor other LHON mutations: the MTND1*LHON3460A mutation in one case and the MTND6*LHON14484A in the other. Hence, the MTCO1*LHON7444A mutation is probably a secondary LHON mutation (Brown and Wallace, 1994). In the 2 families that harbored this mutation, between 23 and 43% of the maternal relatives were affected with all the affected individuals being male (Brown, Lott and Wallace, unpublished data). Pandya et al. (1999) reported 6 unrelated Mongolian deaf students with cosegregation of a 7444G-A mutation and a 1555A-G mutation in the MTRNR1 gene (561000.0001). Five of the individuals had a family history consistent with matrilineal transmission of hearing loss (500008). Only 2 individuals had a definite history of aminoglycoside exposure, but all 6 had severe to profound bilateral sensorineural hearing loss detected at birth or in infancy. Pandya et al. (1999) suggested that the 7444G-A mutation would share a common pathogenic mechanism as the adjacent 7445A-G mutation (590080.0002) in the MTTS1 gene, which results in aberrant processing of the tRNA-ser(UCN) precursor (see Guan et al., 1998). Yuan et al. (2005) reported cosegregation of a homoplasmic 7444G-A mutation and a homoplasmic 1555A-G MTRNR1 mutation in a 3-generation Chinese family with aminoglycoside-induced sensorineural hearing loss (580000). One additional family member with both mutations, who had a history of exposure to noise but not to aminoglycoside, exhibited mild hearing impairment. The dosage and age at the time of drug administration seemed to be correlated with the severity of the hearing loss. (less)
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Pathogenic
(Sep 14, 2007)
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no assertion criteria provided
Method: literature only
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DEAFNESS, AMINOGLYCOSIDE-INDUCED
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000030403.2
First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2022 |
Comment on evidence:
Jin et al. (2007) identified a 7444G-A transition in the MTTS1 gene in 7 of 1,542 Han Chinese individuals with aminoglycoside ototoxicity (580000) or nonsyndromic … (more)
Jin et al. (2007) identified a 7444G-A transition in the MTTS1 gene in 7 of 1,542 Han Chinese individuals with aminoglycoside ototoxicity (580000) or nonsyndromic sensorineural hearing loss. All 7 probands had been administered aminoglycosides between 1 to 3 years of age and began suffering hearing loss within 3 months. Two of the probands had both 7444G-A and a mutation in the MTRNR1 gene (1555A-G; 561000.0001). Family histories suggested very low penetrance for the 7444G-A mutation alone. In contrast, there were several members of the 2 families with both 7444G-A and 1555A-G who had sensorineural hearing loss without aminoglycoside exposure, indicating a higher penetrance of hearing loss in those with 2 mutations. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Mitochondrial non-syndromic sensorineural hearing loss
Affected status: unknown
Allele origin:
maternal
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GeneReviews
Accession: SCV000172234.3
First in ClinVar: Oct 11, 2015 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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Nonsyndromic Hearing Loss and Deafness, Mitochondrial. | Adam MP | - | 2018 | PMID: 20301595 |
Mitochondrial tRNASer(UCN) gene is the hot spot for mutations associated with aminoglycoside-induced and non-syndromic hearing loss. | Jin L | Biochemical and biophysical research communications | 2007 | PMID: 17659260 |
Cosegregation of the G7444A mutation in the mitochondrial COI/tRNA(Ser(UCN)) genes with the 12S rRNA A1555G mutation in a Chinese family with aminoglycoside-induced and nonsyndromic hearing loss. | Yuan H | American journal of medical genetics. Part A | 2005 | PMID: 16152638 |
Heterogenous point mutations in the mitochondrial tRNA Ser(UCN) precursor coexisting with the A1555G mutation in deaf students from Mongolia. | Pandya A | American journal of human genetics | 1999 | PMID: 10577941 |
The deafness-associated mitochondrial DNA mutation at position 7445, which affects tRNASer(UCN) precursor processing, has long-range effects on NADH dehydrogenase subunit ND6 gene expression. | Guan MX | Molecular and cellular biology | 1998 | PMID: 9742104 |
Phylogenetic analysis of Leber's hereditary optic neuropathy mitochondrial DNA's indicates multiple independent occurrences of the common mutations. | Brown MD | Human mutation | 1995 | PMID: 8680405 |
Molecular basis of mitochondrial DNA disease. | Brown MD | Journal of bioenergetics and biomembranes | 1994 | PMID: 8077181 |
Association of deletion and homoplasmic point mutation of the mitochondrial DNA in an ocular myopathy. | Reynier P | Biochemical and biophysical research communications | 1994 | PMID: 8060346 |
Cytochrome c oxidase mutations in Leber hereditary optic neuropathy. | Johns DR | Biochemical and biophysical research communications | 1993 | PMID: 8240356 |
Mitochondrial DNA complex I and III mutations associated with Leber's hereditary optic neuropathy. | Brown MD | Genetics | 1992 | PMID: 1732158 |
Leber's hereditary optic neuropathy: a model for mitochondrial neurodegenerative diseases. | Brown MD | FASEB journal : official publication of the Federation of American Societies for Experimental Biology | 1992 | PMID: 1634041 |
A mitochondrial DNA variant, identified in Leber hereditary optic neuropathy patients, which extends the amino acid sequence of cytochrome c oxidase subunit I. | Brown MD | American journal of human genetics | 1992 | PMID: 1322638 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/095705f0-a498-418a-9d99-84bd4e993b83 | - | - | - | - |
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Text-mined citations for rs199474822 ...
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.