ClinVar Genomic variation as it relates to human health
NM_152269.5(MTRFR):c.210del (p.Gly72fs)
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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NM_152269.5(MTRFR):c.210del (p.Gly72fs)
Variation ID: 54 Accession: VCV000000054.47
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 12q24.31 12: 123253884 (GRCh38) [ NCBI UCSC ] 12: 123738431 (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 Oct 9, 2016 May 12, 2024 Jan 22, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_152269.5:c.210del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_689482.1:p.Gly72fs frameshift NM_001143905.2:c.210del NP_001137377.1:p.Gly72fs frameshift NM_001194995.1:c.210del NP_001181924.1:p.Gly72fs frameshift NM_152269.4:c.210delA NC_000012.12:g.123253884del NC_000012.11:g.123738431del NG_027517.1:g.25588del - Protein change
- G72fs
- Other names
- MTRFR, 1-BP DEL, 210A
- Canonical SPDI
- NC_000012.12:123253883: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.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00010
The Genome Aggregation Database (gnomAD) 0.00016
Exome Aggregation Consortium (ExAC) 0.00018
The Genome Aggregation Database (gnomAD), exomes 0.00018
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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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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MTRFR | - | - |
GRCh38 GRCh37 |
163 | 199 |
Conditions - Germline
Condition
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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
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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/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Oct 19, 2022 | RCV000000071.17 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Sep 1, 2023 | RCV000200775.33 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 22, 2024 | RCV001382822.4 |
Submissions - Germline
Classification
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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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Likely pathogenic
(Aug 23, 2018)
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criteria provided, single submitter
Method: clinical testing
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Combined oxidative phosphorylation defect type 7
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000915580.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The C12orf65 c.210delA (p.Gly72AlafsTer13) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Gly72AlafsTer13 variant has been … (more)
The C12orf65 c.210delA (p.Gly72AlafsTer13) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Gly72AlafsTer13 variant has been reported in three studies and is found in four probands with combined oxidative phosphorylation deficiency (COXPD) including in two in a homozygous state and in two siblings in a compound heterozygous state (Antonicka et al. 2010; Heidary et al. 2014; Wesolowska et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.00032 in the European (non-Finnish) population of the Exome Aggregation Consortium. The p.Gly72AlafsTer13 variant resulted in reduced complex IV activity and reduced quantities of complex I, IV, and V in proband fibroblasts (Antonicka et al. 2010; Heidary et al. 2014; Wesolowska et al. 2015). Based on the potential impact of frameshift variants and available evidence, the p.Gly72AlafsTer13 variant is classified as pathogenic for combined oxidative phosphorylation deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Dec 19, 2016)
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criteria provided, single submitter
Method: clinical testing
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Combined oxidative phosphorylation defect type 7
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000731312.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The p.Gly72AlafsX13 variant in C12orf65 has been reported in 2 homozygous and 1 compound heterozygous probands with clinical features of combined oxidative phos phorylation deficiency … (more)
The p.Gly72AlafsX13 variant in C12orf65 has been reported in 2 homozygous and 1 compound heterozygous probands with clinical features of combined oxidative phos phorylation deficiency type 7 (COXPD7) and segregated with disease in one additi onal affected sibling (Antonika 2010, Heidary 2013, Wesolowska 2015). This varia nt has also been identified in 1/8254 of European chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs57646274). This variant is predicted to cause a frameshift, which alters the protein?s amino aci d sequence beginning at position 72 and leads to a premature termination codon 1 3 amino acids downstream. This alteration is then predicted to lead to a truncat ed or absent protein. Biallelic loss of function of the C12orf65 gene has been a ssociated with COXPD7. In summary, this variant meets criteria to be classified as pathogenic for COXPD7 in an autosomal recessive manner based upon its occurr ence in affected individuals and predicted functional impact. (less)
Number of individuals with the variant: 1
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Pathogenic
(Oct 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Combined oxidative phosphorylation defect type 7
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002600594.1
First in ClinVar: Nov 19, 2022 Last updated: Nov 19, 2022 |
Comment:
Variant summary: C12orf65 c.210delA (p.Gly72AlafsX13) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: C12orf65 c.210delA (p.Gly72AlafsX13) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. One study of C12orf65 mRNA from a homozygous patient showed the level of the C12orf65 mRNA was not significantly reduced, suggesting that nonsense-mediated mRNA decay does not contribute to the loss of function of the C12orf65 gene product (Antonicka_2010). Truncations downstream of this position have been reported with various Mitochondrial disorders in HGMD. The variant allele was found at a frequency of 0.00018 in 251348 control chromosomes. c.210delA has been reported in the literature in multiple individuals affected mitochondrial disorders including Leigh syndrome, optic atrophy, and ophthalmoplegia (examples: Antonicka_2010, Heidary_2014, Wesolowska_2015, Schon_2021). These data indicate that the variant is very likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Dec 17, 2021)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000802804.2
First in ClinVar: Aug 05, 2018 Last updated: Jun 03, 2023 |
Comment:
PP1, PM2, PM3, PVS1
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Pathogenic
(Jul 05, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000251229.17
First in ClinVar: Oct 11, 2015 Last updated: Jul 16, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation, as the last 95 amino acids are replaced with 12 different amino acids, and other loss-of-function variants … (more)
Frameshift variant predicted to result in protein truncation, as the last 95 amino acids are replaced with 12 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 20598281, 24284555, 27858754, 30609409, 36344503) (less)
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Pathogenic
(Sep 23, 2020)
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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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Revvity Omics, Revvity
Accession: SCV002018008.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 22, 2024)
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criteria provided, single submitter
Method: clinical testing
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Combined oxidative phosphorylation defect type 7
Spastic paraplegia
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001581757.4
First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gly72Alafs*13) in the C12orf65 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Gly72Alafs*13) in the C12orf65 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 95 amino acid(s) of the C12orf65 protein. This variant is present in population databases (rs576462794, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with clinical features of C12orf65-related conditions (PMID: 20598281, 24284555, 27858754). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 54). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001502153.18
First in ClinVar: Mar 14, 2021 Last updated: May 12, 2024 |
Comment:
MTRFR: PVS1, PM2, PM3
Number of individuals with the variant: 3
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001741202.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Pathogenic
(Jul 09, 2010)
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no assertion criteria provided
Method: literature only
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COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 7
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000020214.5
First in ClinVar: Apr 04, 2013 Last updated: Dec 31, 2022 |
Comment on evidence:
In 2 Dutch brothers with combined oxidative phosphorylation deficiency-7 (COXPD7; 613559), Antonicka et al. (2010) identified a homozygous 1-bp deletion (210delA) in exon 2 of … (more)
In 2 Dutch brothers with combined oxidative phosphorylation deficiency-7 (COXPD7; 613559), Antonicka et al. (2010) identified a homozygous 1-bp deletion (210delA) in exon 2 of the C12ORF65 gene, resulting in premature termination at codon 84. Both boys had psychomotor regression in childhood, followed by optic atrophy, nystagmus, and bulbar paresis. Other features included an axonal polyneuropathy, muscle hypotonia and atrophy, and brain lesions in 1. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001975716.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Combined oxidative phosphorylation defect type 7
Affected status: yes
Allele origin:
germline
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GenomeConnect, ClinGen
Accession: SCV002818348.1
First in ClinVar: Jan 07, 2023 Last updated: Jan 07, 2023 |
Comment:
Variant classified as Pathogenic and reported on 10-10-2014 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more)
Variant classified as Pathogenic and reported on 10-10-2014 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Lactic acidosis (present) , Developmental regression (present) , Sensorineural hearing loss disorder (present) , Abnormal brain morphology (present) , Muscle weakness (present) , Hyper-beta-alaninemia (present)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: male
Method: Gene Panel Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2014-10-10
Testing laboratory interpretation: Pathogenic
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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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Use of whole genome sequencing to determine genetic basis of suspected mitochondrial disorders: cohort study. | Schon KR | BMJ (Clinical research ed.) | 2021 | PMID: 34732400 |
Adult Onset Leigh Syndrome in the Intensive Care Setting: A Novel Presentation of a C12orf65 Related Mitochondrial Disease. | Wesolowska M | Journal of neuromuscular diseases | 2015 | PMID: 27858754 |
Optic atrophy and a Leigh-like syndrome due to mutations in the c12orf65 gene: report of a novel mutation and review of the literature. | Heidary G | Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society | 2014 | PMID: 24284555 |
A systematic approach to assessing the clinical significance of genetic variants. | Duzkale H | Clinical genetics | 2013 | PMID: 24033266 |
Mutations in C12orf65 in patients with encephalomyopathy and a mitochondrial translation defect. | Antonicka H | American journal of human genetics | 2010 | PMID: 20598281 |
Text-mined citations for rs576462794 ...
HelpRecord last updated May 12, 2024
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.