The NM_012160.4:c.292C>T (NP_036292.2:p.Arg98Ter) [GRCH38: NC_000006.12:g.98926697G>A] variant in FBXL4 gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:27099744 . This variant meets one or more of the following evidence codes reported in the ACMG-guideline. PVS1:This variant is a predcted null variant in FBXL4 where loss of function is a known mechanism of disease. PM2:This variant is absent in key population databases. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 13 which is a recessive disorder. PP4:Patient’s phenotype or family history is highly specific for FBXL4. PP5:Reputable source(s) suggest that the variant is pathogenic. Based on this evidence code ClinGen Pathogenicity Calculator (PMID:28081714) suggested that the variant is Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_001278716.2(FBXL4):c.292C>T (p.Arg98Ter)
Germline
Classification
Help
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.
(8)
Help
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/Likely pathogenic
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001278716.2(FBXL4):c.292C>T (p.Arg98Ter)
Variation ID: 437490 Accession: VCV000437490.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6q16.2 6: 98926697 (GRCh38) [ NCBI UCSC ] 6: 99374573 (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 Aug 28, 2017 Oct 26, 2024 Jun 10, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001278716.2:c.292C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001265645.1:p.Arg98Ter nonsense NM_012160.3:c.292C>T NM_012160.5:c.292C>T NP_036292.2:p.Arg98Ter nonsense NR_103836.2:n.623C>T non-coding transcript variant NR_103837.2:n.623C>T non-coding transcript variant NC_000006.12:g.98926697G>A NC_000006.11:g.99374573G>A NG_033903.1:g.26310C>T - Protein change
- R98*
- Other names
- -
- Canonical SPDI
- NC_000006.12:98926696: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
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD) 0.00001
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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. |
|||
| FBXL4 | - | - |
GRCh38 GRCh37 |
572 | 597 | |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Jun 10, 2024 | RCV000501775.10 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Apr 23, 2024 | RCV001280758.5 |
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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|---|---|---|---|---|---|
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Pathogenic
(Aug 10, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial DNA depletion syndrome 13
Affected status: yes
Allele origin:
germline
|
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine
Accession: SCV000598183.1
First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017 |
Comment:
The NM_012160.4:c.292C>T (NP_036292.2:p.Arg98Ter) [GRCH38: NC_000006.12:g.98926697G>A] variant in FBXL4 gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been … (more)
The NM_012160.4:c.292C>T (NP_036292.2:p.Arg98Ter) [GRCH38: NC_000006.12:g.98926697G>A] variant in FBXL4 gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:27099744 . This variant meets one or more of the following evidence codes reported in the ACMG-guideline. PVS1:This variant is a predcted null variant in FBXL4 where loss of function is a known mechanism of disease. PM2:This variant is absent in key population databases. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 13 which is a recessive disorder. PP4:Patient’s phenotype or family history is highly specific for FBXL4. PP5:Reputable source(s) suggest that the variant is pathogenic. Based on this evidence code ClinGen Pathogenicity Calculator (PMID:28081714) suggested that the variant is Pathogenic. (less)
|
|
|
Pathogenic
(Aug 26, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV001468078.1
First in ClinVar: Jan 07, 2021 Last updated: Jan 07, 2021 |
Comment on evidence:
PVS1, PS4_Moderate, PM2
|
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial DNA depletion syndrome 13
Affected status: yes
Allele origin:
germline
|
Pathology and Clinical Laboratory Medicine, King Fahad Medical City
Accession: SCV002073799.1
First in ClinVar: Feb 10, 2022 Last updated: Feb 10, 2022 |
Number of individuals with the variant: 1
Ethnicity/Population group: Arab
Geographic origin: Middle East
|
|
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Pathogenic
(Feb 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial DNA depletion syndrome 13
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004041000.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
|
|
|
Pathogenic
(Sep 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial DNA depletion syndrome 13
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002023053.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jun 10, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial DNA depletion syndrome 13
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005204918.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
Comment:
Variant summary: FBXL4 c.292C>T (p.Arg98X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: FBXL4 c.292C>T (p.Arg98X) 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, which are commonly known mechanisms for disease. The variant was absent in 251384 control chromosomes. c.292C>T has been reported in the literature in homozygous or compound heterozygous individuals affected with Mitochondrial DNA Depletion Syndrome 13 (encephalomyopathic Type) (van Rij_2016, Trujillano_2017, Theunissen_2018, Monies_2019). 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. The following publications have been ascertained in the context of this evaluation (PMID: 31130284, 30369941, 27848944, 27099744). ClinVar contains an entry for this variant (Variation ID: 437490). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
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Pathogenic
(Apr 23, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002015554.3
First in ClinVar: Nov 20, 2021 Last updated: Sep 29, 2024 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30804983, 30369941, 31130284, 35750291, 28940506, 27099744) (less)
|
|
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Likely pathogenic
(Jun 01, 2022)
|
no assertion criteria provided
Method: provider interpretation
|
Mitochondrial DNA depletion syndrome 13
Affected status: yes
Allele origin:
inherited
|
Solve-RD Consortium
Accession: SCV005091546.1
First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024
Comment:
Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and … (more)
Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. (less)
|
Comment:
Variant confirmed as disease-causing by referring clinical team
|
Comment:
Comment:
Variant summary: FBXL4 c.292C>T (p.Arg98X) 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, which are commonly known mechanisms for disease. The variant was absent in 251384 control chromosomes. c.292C>T has been reported in the literature in homozygous or compound heterozygous individuals affected with Mitochondrial DNA Depletion Syndrome 13 (encephalomyopathic Type) (van Rij_2016, Trujillano_2017, Theunissen_2018, Monies_2019). 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. The following publications have been ascertained in the context of this evaluation (PMID: 31130284, 30369941, 27848944, 27099744). ClinVar contains an entry for this variant (Variation ID: 437490). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30804983, 30369941, 31130284, 35750291, 28940506, 27099744)
Comment:
Variant confirmed as disease-causing by referring clinical team
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. |
Comment:
The NM_012160.4:c.292C>T (NP_036292.2:p.Arg98Ter) [GRCH38: NC_000006.12:g.98926697G>A] variant in FBXL4 gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:27099744 . This variant meets one or more of the following evidence codes reported in the ACMG-guideline. PVS1:This variant is a predcted null variant in FBXL4 where loss of function is a known mechanism of disease. PM2:This variant is absent in key population databases. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 13 which is a recessive disorder. PP4:Patient’s phenotype or family history is highly specific for FBXL4. PP5:Reputable source(s) suggest that the variant is pathogenic. Based on this evidence code ClinGen Pathogenicity Calculator (PMID:28081714) suggested that the variant is Pathogenic.
Comment:
Variant summary: FBXL4 c.292C>T (p.Arg98X) 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, which are commonly known mechanisms for disease. The variant was absent in 251384 control chromosomes. c.292C>T has been reported in the literature in homozygous or compound heterozygous individuals affected with Mitochondrial DNA Depletion Syndrome 13 (encephalomyopathic Type) (van Rij_2016, Trujillano_2017, Theunissen_2018, Monies_2019). 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. The following publications have been ascertained in the context of this evaluation (PMID: 31130284, 30369941, 27848944, 27099744). ClinVar contains an entry for this variant (Variation ID: 437490). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30804983, 30369941, 31130284, 35750291, 28940506, 27099744)
Comment:
Variant confirmed as disease-causing by referring clinical team
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population. | Monies D | American journal of human genetics | 2019 | PMID: 31130284 |
| Whole Exome Sequencing Is the Preferred Strategy to Identify the Genetic Defect in Patients With a Probable or Possible Mitochondrial Cause. | Theunissen TEJ | Frontiers in genetics | 2018 | PMID: 30369941 |
| Clinical exome sequencing: results from 2819 samples reflecting 1000 families. | Trujillano D | European journal of human genetics : EJHG | 2017 | PMID: 27848944 |
| Polyhydramnios and cerebellar atrophy: a prenatal presentation of mitochondrial encephalomyopathy caused by mutations in the FBXL4 gene. | van Rij MC | Clinical case reports | 2016 | PMID: 27099744 |
Text-mined citations for rs1554222130 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 27, 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.