VCV000265143.10 - ClinVar

NM_001278716.2(FBXL4):c.1641_1642del (p.Cys547_Asp548delinsTer)

Germline

Classification

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.

(5)

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

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.1641_1642del (p.Cys547_Asp548delinsTer)

Variation ID: 265143 Accession: VCV000265143.10

Type and length

Microsatellite, 2 bp

Location

Cytogenetic: 6q16.1 6: 98875475-98875476 (GRCh38) [ NCBI UCSC ] 6: 99323351-99323352 (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	Oct 10, 2016	Feb 14, 2024	Dec 26, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001278716.2:c.1641_1642del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001265645.1:p.Cys547_Asp548delinsTer	nonsense
NM_012160.3:c.1641_1642delTG
NM_012160.4:c.1641_1642del
NM_012160.5:c.1641_1642del	NP_036292.2:p.Cys547_Asp548delinsTer	nonsense
NR_103836.2:n.1620TG[3]		non-coding transcript variant
NC_000006.12:g.98875475CA[3]
NC_000006.11:g.99323351CA[3]
NG_033903.1:g.77525TG[3]

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000006.12:98875474:CACACACA:CACACA

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Links

ClinGen: CA3933411 dbSNP: rs765882664 VarSome

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
Gene	OMIM	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	573	598

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.
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 26, 2023	RCV000255233.7
Mitochondrial DNA depletion syndrome 13	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Feb 16, 2023	RCV000500450.6

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 (Aug 10, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) 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: SCV000598194.1 First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017	Publications: PubMed (2) PubMed: 25868664‚ 27743463 Comment: The NM_012160.4:c.1641_1642del (NP_036292.2:p.Cys547Ter) [GRCH38: NC_000006.12:g.98875481_98875482del] 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.1641_1642del (NP_036292.2:p.Cys547Ter) [GRCH38: NC_000006.12:g.98875481_98875482del] variant in FBXL4 gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:25868664 ; 27743463 . 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:Patientâ€™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, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000321634.9 First in ClinVar: Oct 10, 2016 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; This … (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; This variant is associated with the following publications: (PMID: 26404457, 26968897, 25868664, 27743463, 30831263, 28940506, 30853194, 30679813, 31984159, 32445240) (less)
Pathogenic (Jan 20, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mitochondrial DNA depletion syndrome 13 Affected status: yes Allele origin: inherited	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV002072557.1 First in ClinVar: Feb 03, 2022 Last updated: Feb 03, 2022	Comment: This variant was identified as homozygous. Parents are both heterozygous Criteria applied: PVS1, PM3, PM2_SUP
Pathogenic (Feb 16, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mitochondrial DNA depletion syndrome 13 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004041091.1 First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023
Pathogenic (Dec 26, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003267750.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 23993193‚ 23993194‚ 25868664‚ 26404457‚ 31984159 Comment: This sequence change creates a premature translational stop signal (p.Cys547) 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.Cys547) 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 (rs765882664, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with mitochondrial DNA depletion syndrome (PMID: 26404457, 31984159). ClinVar contains an entry for this variant (Variation ID: 265143). For these reasons, this variant has been classified as Pathogenic. (less)

Comment:

The NM_012160.4:c.1641_1642del (NP_036292.2:p.Cys547Ter) [GRCH38: NC_000006.12:g.98875481_98875482del] variant in FBXL4 gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:25868664 ; 27743463 . 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:Patientâ€™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:

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: 26404457, 26968897, 25868664, 27743463, 30831263, 28940506, 30853194, 30679813, 31984159, 32445240)

Comment:

This sequence change creates a premature translational stop signal (p.Cys547*) 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 (rs765882664, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with mitochondrial DNA depletion syndrome (PMID: 26404457, 31984159). ClinVar contains an entry for this variant (Variation ID: 265143). For these reasons, this variant has been classified as Pathogenic.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Fulminant Necrotizing Enterocolitis and Multiple Organ Dysfunction in a Toddler with Mitochondrial DNA Depletion Syndrome-13.	Nardi N	Journal of pediatric intensive care	2020	PMID: 31984159
FBXL4 defects are common in patients with congenital lactic acidemia and encephalomyopathic mitochondrial DNA depletion syndrome.	Dai H	Clinical genetics	2017	PMID: 27743463
Detailed Biochemical and Bioenergetic Characterization of FBXL4-Related Encephalomyopathic Mitochondrial DNA Depletion.	Antoun G	JIMD reports	2016	PMID: 26404457
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

Text-mined citations for rs765882664 ...

These 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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001278716.2(FBXL4):c.1641_1642del (p.Cys547_Asp548delinsTer)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs765882664 ...