ClinVar Genomic variation as it relates to human health
NM_017547.4(FOXRED1):c.733+1G>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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NM_017547.4(FOXRED1):c.733+1G>A
Variation ID: 1705022 Accession: VCV001705022.4
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q24.2 11: 126275429 (GRCh38) [ NCBI UCSC ] 11: 126145324 (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 Sep 17, 2022 Apr 15, 2024 Apr 4, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_017547.4:c.733+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NC_000011.10:g.126275429G>A NC_000011.9:g.126145324G>A NG_028029.1:g.11390G>A - Protein change
- Other names
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- Canonical SPDI
- NC_000011.10:126275428: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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- Links
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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FOXRED1 | - | - |
GRCh38 GRCh37 |
425 | 530 |
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
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/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Apr 4, 2024 | RCV002283347.5 | |
Pathogenic (1) |
criteria provided, single submitter
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May 16, 2023 | RCV003728066.1 |
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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Pathogenic
(Aug 31, 2019)
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criteria provided, single submitter
Method: clinical testing, in vitro
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Mitochondrial complex 1 deficiency, nuclear type 19
Affected status: not applicable, yes
Allele origin:
maternal,
not applicable
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Diagnostic and Treatment Unit for Congenital Metabolic Diseases, Hopital Clínico Universitario de Santiago de Compostela (CHUS)
Accession: SCV002571712.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Observation 1:
Clinical Features:
Lactic acidosis (present) , hypotonia (present) , neurodevelopmental delay (present) , refractory epilepsy (present)
Family history: yes
Segregation observed: yes
Observation 2:
Tissue: Blood, fibroblasts
Method: Mitochondrial respiration and OXPHOS activity; SDS-PAGE and BN-PAGE immunoblot analysis
Result:
The molecular characterization using patient’s fibroblasts clearly demonstrated a mitochondrial dysfunction due to abnormal mitochondrial respiration with a significant decrease of the OCR/ECAR ratio, OXPHOS activity and reduced complex I.
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Likely pathogenic
(Nov 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex 1 deficiency, nuclear type 19
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002766399.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Variant summary: FOXRED1 c.733+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more)
Variant summary: FOXRED1 c.733+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-05 in 250948 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in FOXRED1 causing Mitochondrial Complex 1 Deficiency, Nuclear Type 19, allowing no conclusion about variant significance. c.733+1G>A has been reported in the literature in a family affected with Mitochondrial Complex 1 Deficiency (Barbosa-Gouveia_2019), and these affected individuals were reported as compound heterozygous with another possibly pathogenic variant. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Pathogenic
(May 16, 2023)
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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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Invitae
Accession: SCV004535561.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more)
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1705022). Disruption of this splice site has been observed in individual(s) with mitochondrial complex I deficiency (PMID: 31434271). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs754952690, gnomAD 0.03%). This sequence change affects a donor splice site in intron 6 of the FOXRED1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FOXRED1 are known to be pathogenic (PMID: 20818383, 20858599). (less)
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Pathogenic
(Apr 04, 2024)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex 1 deficiency, nuclear type 19
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004809566.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
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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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Rapid Molecular Diagnosis of Genetically Inherited Neuromuscular Disorders Using Next-Generation Sequencing Technologies. | Barbosa-Gouveia S | Journal of clinical medicine | 2022 | PMID: 35628876 |
Identification and Characterization of New Variants in FOXRED1 Gene Expands the Clinical Spectrum Associated with Mitochondrial Complex I Deficiency. | Barbosa-Gouveia S | Journal of clinical medicine | 2019 | PMID: 31434271 |
FOXRED1, encoding an FAD-dependent oxidoreductase complex-I-specific molecular chaperone, is mutated in infantile-onset mitochondrial encephalopathy. | Fassone E | Human molecular genetics | 2010 | PMID: 20858599 |
High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency. | Calvo SE | Nature genetics | 2010 | PMID: 20818383 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Text-mined citations for this variant ...
HelpRecord last updated Aug 04, 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.