ClinVar Genomic variation as it relates to human health
NM_001278716.2(FBXL4):c.64C>T (p.Arg22Ter)
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
-
NM_001278716.2(FBXL4):c.64C>T (p.Arg22Ter)
Variation ID: 209153 Accession: VCV000209153.21
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 6q16.2 6: 98926925 (GRCh38) [ NCBI UCSC ] 6: 99374801 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 29, 2015 Feb 14, 2024 Dec 15, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_001278716.2:c.64C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001265645.1:p.Arg22Ter nonsense NM_012160.5:c.64C>T NP_036292.2:p.Arg22Ter nonsense NR_103836.2:n.395C>T non-coding transcript variant NR_103837.2:n.395C>T non-coding transcript variant NC_000006.12:g.98926925G>A NC_000006.11:g.99374801G>A NG_033903.1:g.26082C>T - Protein change
- R22*
- Other names
- -
- Canonical SPDI
- NC_000006.12:98926924:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00004
The Genome Aggregation Database (gnomAD) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00008
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 |
566 | 591 |
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 (5) |
criteria provided, multiple submitters, no conflicts
|
Mar 23, 2022 | RCV000191084.7 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Dec 15, 2023 | RCV000578719.15 | |
Pathogenic (1) |
criteria provided, single submitter
|
May 24, 2018 | RCV001267292.3 | |
Pathogenic (1) |
criteria provided, single submitter
|
- | RCV002273980.1 |
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. |
|
---|---|---|---|---|---|
Pathogenic
(Jan 27, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type)
(Autosomal recessive inheritance)
Affected status: unknown, yes
Allele origin:
germline
|
Baylor Genetics
Study: Adult_WES
Accession: SCV000245480.1 First in ClinVar: Sep 29, 2015 Last updated: Sep 29, 2015 |
Comment:
This nonsense variant is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found once in our laboratory homozygous in a 32-year-old male with … (more)
This nonsense variant is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found once in our laboratory homozygous in a 32-year-old male with intellectual disability, hypotonia, dragging of right foot when walking, tremors, dysmorphisms, hyperextensibility, failure to thrive, amblyopia, myopia, mitral valve prolapse, scoliosis, serial episodes of lactic acidosis, white matter abnormalities. Variant pathogenic in recessive state; heterozygotes are carriers. (less)
Observation 1:
Number of individuals with the variant: 1
Age: 30-39 years
Sex: male
Ethnicity/Population group: Causasians
Observation 2:
Number of individuals with the variant: 2
Age: 0-9 years
Sex: female
|
|
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: SCV000598180.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
The NM_012160.4:c.64C>T (NP_036292.2:p.Arg22Ter) [GRCH38: NC_000006.12:g.98926925G>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.64C>T (NP_036292.2:p.Arg22Ter) [GRCH38: NC_000006.12:g.98926925G>A] variant in FBXL4 gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:27743463 ; 27290639 . 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
(Feb 02, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000339107.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
Pathogenic
(Apr 16, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial DNA depletion syndrome 13
Affected status: yes
Allele origin:
inherited
|
Department of Molecular and Human Genetics, Baylor College of Medicine
Accession: SCV001334104.1
First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020 |
Comment on evidence:
in trans with FBXL4 exons 3-6 deletion
|
|
Pathogenic
(Aug 29, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002064325.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
|
|
Likely pathogenic
(Jan 28, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial DNA depletion syndrome 13
Affected status: yes
Allele origin:
maternal
|
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine
Accession: SCV002102904.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
Sex: female
|
|
Pathogenic
(May 24, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001445473.2
First in ClinVar: Nov 21, 2020 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Global developmental delay (present) , Intellectual disability (present) , Autistic disorder of childhood onset (present) , Behavioral abnormality (present) , Parkinsonism (present) , Dystonia (present) … (more)
Global developmental delay (present) , Intellectual disability (present) , Autistic disorder of childhood onset (present) , Behavioral abnormality (present) , Parkinsonism (present) , Dystonia (present) , Cerebellar atrophy (present) , Muscular hypotonia (present) , Brisk reflexes (present) , Osteoporosis (present) , Scoliosis (present) , Hypospadias, penile (present) , Lactic acidosis (present) , Increased CSF lactate (present) , Elevated plasma acylcarnitine levels (present) (less)
Sex: male
|
|
Pathogenic
(May 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000680951.5
First in ClinVar: Feb 13, 2018 Last updated: Mar 04, 2023 |
Comment:
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; Not … (more)
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; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27290639, 27743463, 28940506, 26633545, 30804983, 32525278, 33726816) (less)
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodevelopmental delay
Affected status: yes
Allele origin:
biparental
|
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Accession: SCV002559092.1
First in ClinVar: Aug 15, 2022 Last updated: Aug 15, 2022 |
|
|
Pathogenic
(Mar 23, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial DNA depletion syndrome 13
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002793830.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
Pathogenic
(Dec 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV003439479.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg22*) in the FBXL4 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg22*) in the FBXL4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FBXL4 are known to be pathogenic (PMID: 23993193, 23993194, 25868664). This variant is present in population databases (rs200440128, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with clinical features of FBXL4-related conditions (PMID: 27290639, 27743463). ClinVar contains an entry for this variant (Variation ID: 209153). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Jul 27, 2017)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes
Accession: SCV000778274.1
First in ClinVar: Jun 02, 2018 Last updated: Jun 02, 2018 |
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
CNVs cause autosomal recessive genetic diseases with or without involvement of SNV/indels. | Yuan B | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32576985 |
Molecular and clinical spectra of FBXL4 deficiency. | El-Hattab AW | Human mutation | 2017 | PMID: 28940506 |
FBXL4 defects are common in patients with congenital lactic acidemia and encephalomyopathic mitochondrial DNA depletion syndrome. | Dai H | Clinical genetics | 2017 | PMID: 27743463 |
New perspective in diagnostics of mitochondrial disorders: two years' experience with whole-exome sequencing at a national paediatric centre. | Pronicka E | Journal of translational medicine | 2016 | PMID: 27290639 |
Molecular diagnostic experience of whole-exome sequencing in adult patients. | Posey JE | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26633545 |
Clinical, morphological, biochemical, imaging and outcome parameters in 21 individuals with mitochondrial maintenance defect related to FBXL4 mutations. | Huemer M | Journal of inherited metabolic disease | 2015 | PMID: 25868664 |
Mutations in FBXL4, encoding a mitochondrial protein, cause early-onset mitochondrial encephalomyopathy. | Gai X | American journal of human genetics | 2013 | PMID: 23993194 |
Mutations in FBXL4 cause mitochondrial encephalopathy and a disorder of mitochondrial DNA maintenance. | Bonnen PE | American journal of human genetics | 2013 | PMID: 23993193 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FBXL4 | - | - | - | - |
Text-mined citations for rs200440128 ...
HelpRecord last updated Feb 20, 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.