ClinVar Genomic variation as it relates to human health
NM_001303.4(COX10):c.311C>T (p.Pro104Leu)
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(6); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001303.4(COX10):c.311C>T (p.Pro104Leu)
Variation ID: 449007 Accession: VCV000449007.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p12 17: 14076868 (GRCh38) [ NCBI UCSC ] 17: 13980185 (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 Dec 19, 2017 Oct 8, 2024 Sep 1, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001303.4:c.311C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001294.2:p.Pro104Leu missense NC_000017.11:g.14076868C>T NC_000017.10:g.13980185C>T NG_008034.1:g.12467C>T - Protein change
- P104L
- Other names
- -
- Canonical SPDI
- NC_000017.11:14076867:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- functionally_normal Sequence Ontology [SO:0002219]
- Functional allele is likely benign for Leigh Syndrome [submitted by Johnston Lab, North Central College]
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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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0.00020 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
1000 Genomes Project 30x 0.00016
The Genome Aggregation Database (gnomAD) 0.00016
Trans-Omics for Precision Medicine (TOPMed) 0.00016
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD), exomes 0.00020
Exome Aggregation Consortium (ExAC) 0.00026
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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COX10 | - | - |
GRCh38 GRCh37 |
249 | 380 |
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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Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Sep 1, 2023 | RCV000521510.22 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 12, 2018 | RCV001127738.11 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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May 15, 2018 | RCV001127737.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 25, 2021 | RCV002476049.8 |
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
(Aug 21, 2017)
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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: SCV000616688.2
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
Comment:
The P104L variant in the COX10 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The … (more)
The P104L variant in the COX10 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The P104L variant is observed in 9/8650 (0.104%) alleles from individuals of East Asian background in the ExAC dataset and no individuals were reported to be homozygous (Lek et al., 2016). The P104L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret P104L as a variant of uncertain significance. (less)
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Uncertain significance
(Jan 12, 2018)
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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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Illumina Laboratory Services, Illumina
Accession: SCV001287080.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
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Uncertain significance
(Jan 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex IV deficiency, nuclear type 1
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001287081.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
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Uncertain significance
(May 15, 2018)
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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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Baylor Genetics
Accession: SCV001526631.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
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Uncertain significance
(Dec 25, 2021)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex 4 deficiency, nuclear type 3
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000895070.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
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Uncertain significance
(Jul 06, 2022)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002284745.2
First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 104 of the COX10 protein (p.Pro104Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 104 of the COX10 protein (p.Pro104Leu). This variant is present in population databases (rs202207627, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with COX10-related conditions. ClinVar contains an entry for this variant (Variation ID: 449007). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Likely benign
(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: SCV004041987.10
First in ClinVar: Oct 14, 2023 Last updated: Oct 08, 2024 |
Comment:
COX10: BP4
Number of individuals with the variant: 1
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not provided
(-)
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no classification provided
Method: in vitro
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not provided
Affected status: not applicable
Allele origin:
not applicable
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Johnston Lab, North Central College
Accession: SCV005200382.1
First in ClinVar: Sep 01, 2024 Last updated: Sep 01, 2024 |
Method: Human COX10 alleles were expressed in yeast lacking the endogenous COX10 to determine how functional the encoded proteins are.
Result:
COX10 activity comparable to reference.
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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functionally_normal
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Method citation(s):
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Johnston Lab, North Central College
Accession: SCV005200382.1
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Comment:
Functional allele is likely benign for Leigh Syndrome
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Phenotypic assessment of Cox10 variants and their implications for Leigh Syndrome. | Voges TS | BMC research notes | 2024 | PMID: 39152498 |
Text-mined citations for rs202207627 ...
HelpRecord last updated Oct 13, 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.