ClinVar Genomic variation as it relates to human health
NM_017547.4(FOXRED1):c.874G>A (p.Gly292Arg)
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.
Pathogenic(3); Likely pathogenic(2); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_017547.4(FOXRED1):c.874G>A (p.Gly292Arg)
Variation ID: 449732 Accession: VCV000449732.27
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q24.2 11: 126276122 (GRCh38) [ NCBI UCSC ] 11: 126146017 (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 May 12, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_017547.4:c.874G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060017.1:p.Gly292Arg missense NR_037647.2:n.706G>A non-coding transcript variant NR_037648.2:n.1051G>A non-coding transcript variant NC_000011.10:g.126276122G>A NC_000011.9:g.126146017G>A NG_028029.1:g.12083G>A - Protein change
- G292R
- Other names
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- Canonical SPDI
- NC_000011.10:126276121: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.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
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 |
420 | 525 |
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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Aug 24, 2023 | RCV000521848.19 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jan 29, 2024 | RCV001264834.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 6, 2021 | RCV002525129.3 |
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
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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
(Jul 17, 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: SCV000618098.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
Comment:
The G292R variant in the FOXRED1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The … (more)
The G292R variant in the FOXRED1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The G292R variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G292R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret G292R as a likely pathogenic variant. (less)
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Uncertain significance
(Mar 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex 1 deficiency, nuclear type 19
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
biparental
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001443036.1
First in ClinVar: Nov 14, 2020 Last updated: Nov 14, 2020 |
Comment:
Review of the variants reported in Reuter et al., 2017, PMID: 28097321: PM2,PM3,PP3
Clinical Features:
moderate ID (present) , seizures (present) , muscular hypotonia (present)
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Pathogenic
(Aug 24, 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: SCV004366832.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 449732). This missense change has been observed in individual(s) with mitochondrial complex I deficiency (PMID: 28097321, … (more)
ClinVar contains an entry for this variant (Variation ID: 449732). This missense change has been observed in individual(s) with mitochondrial complex I deficiency (PMID: 28097321, 30723688, 31065540, 33726816). 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 (rs749110767, gnomAD 0.006%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 292 of the FOXRED1 protein (p.Gly292Arg). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FOXRED1 protein function. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 29, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004803969.1
First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024 |
Comment:
Variant summary: FOXRED1 c.874G>A (p.Gly292Arg) results in a non-conservative amino acid change to a highly conserved residue (HGMD) located in the FAD dependent oxidoreductase domain … (more)
Variant summary: FOXRED1 c.874G>A (p.Gly292Arg) results in a non-conservative amino acid change to a highly conserved residue (HGMD) located in the FAD dependent oxidoreductase domain (IPR006076) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 248526 control chromosomes (gnomAD). c.874G>A has been reported in the literature in multiple individuals affected with Mitochondrial Complex 1 Deficiency, both in the homozygous state and in the compound heterozygous state with a pathogenic variant (Reuter_2017, Apatean_2019, Stodberg_2020). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 28097321, 30723688, 32964447). ClinVar contains an entry for this variant (Variation ID: 449732). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Dec 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003595136.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.874G>A (p.G292R) alteration is located in exon 8 (coding exon 8) of the FOXRED1 gene. This alteration results from a G to A substitution … (more)
The c.874G>A (p.G292R) alteration is located in exon 8 (coding exon 8) of the FOXRED1 gene. This alteration results from a G to A substitution at nucleotide position 874, causing the glycine (G) at amino acid position 292 to be replaced by an arginine (R). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (3/248526) total alleles studied. The highest observed frequency was 0.01% (1/18328) of East Asian alleles. This alteration has been reported in the homozygous and compound heterozygous states in individuals with features consistent with FOXRED1-related mitochondrial complex I deficiency (Apatean, 2019; Stödberg, 2020; Reuter, 2017). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. (less)
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Pathogenic
(Jun 01, 2020)
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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: SCV001371573.19
First in ClinVar: Jul 16, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 3
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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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Integration of whole genome sequencing into a healthcare setting: high diagnostic rates across multiple clinical entities in 3219 rare disease patients. | Stranneheim H | Genome medicine | 2021 | PMID: 33726816 |
Epilepsy syndromes, etiologies, and the use of next-generation sequencing in epilepsy presenting in the first 2 years of life: A population-based study. | Stödberg T | Epilepsia | 2020 | PMID: 32964447 |
Congenital lactic acidosis, cerebral cysts and pulmonary hypertension in an infant with FOXRED1 related complex 1 deficiency. | Apatean D | Molecular genetics and metabolism reports | 2019 | PMID: 31065540 |
Congenital lactic acidosis, cerebral cysts and pulmonary hypertension in an infant with FOXRED1 related complex I deficiency. | Apatean D | Molecular genetics and metabolism reports | 2019 | PMID: 30723688 |
Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders. | Reuter MS | JAMA psychiatry | 2017 | PMID: 28097321 |
Text-mined citations for rs749110767 ...
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.