VCV000375387.5 - ClinVar

NM_001278716.2(FBXL4):c.419T>C (p.Val140Ala)

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/Likely 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.419T>C (p.Val140Ala)

Variation ID: 375387 Accession: VCV000375387.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6q16.2 6: 98926570 (GRCh38) [ NCBI UCSC ] 6: 99374446 (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	Feb 4, 2017	Sep 29, 2024	Dec 25, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001278716.2:c.419T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001265645.1:p.Val140Ala	missense
NM_012160.3:c.419T>C
NM_012160.5:c.419T>C	NP_036292.2:p.Val140Ala	missense
NR_103836.2:n.750T>C		non-coding transcript variant
NR_103837.2:n.750T>C		non-coding transcript variant
NC_000006.12:g.98926570A>G
NC_000006.11:g.99374446A>G
NG_033903.1:g.26437T>C

... more HGVS ... less HGVS

Protein change

V140A

Other names

Canonical SPDI

NC_000006.12:98926569:A:G

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.

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Links

ClinGen: CA16020684 dbSNP: rs1057519447 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	574	599

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.
Mitochondrial DNA depletion syndrome 13	Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	May 28, 2019	RCV000416414.5
not provided	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 25, 2023	RCV002521494.3

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 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.
Likely 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: SCV000598156.1 First in ClinVar: Feb 04, 2017 Last updated: Feb 04, 2017	Comment: The NM_012160.4:c.419T>C (NP_036292.2:p.Val140Ala) [GRCH38: NC_000006.12:g.98926570A>G] variant in FBXL4 gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant meets … (more) The NM_012160.4:c.419T>C (NP_036292.2:p.Val140Ala) [GRCH38: NC_000006.12:g.98926570A>G] variant in FBXL4 gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant meets one or more of the following evidence codes reported in the ACMG-guideline. 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. PP2:This is a missense variant in FBXL4 with a low rate of benign and high rate of pathogenic missense variations. PP3:Computational evidence/predictors indicate the variant has deleterious effect on FBXL4 structure, function, or protein-protein interaction. PP4:Patientâ€™s phenotype or family history is highly specific for FBXL4. Based on this evidence code ClinGen Pathogenicity Calculator (PMID:28081714) suggested that the variant is Likely Pathogenic. (less)
Likely pathogenic (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Mitochondrial DNA depletion syndrome 13 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001137199.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Likely pathogenic (Dec 25, 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: SCV003440004.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 28327206‚ 28940506 Comment: This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 140 of the FBXL4 protein (p.Val140Ala). … (more) This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 140 of the FBXL4 protein (p.Val140Ala). This variant is present in population databases (no rsID available, gnomAD 0.009%). This missense change has been observed in individuals with clinical features of mitochondrial DNA depletion syndrome (PMID: 28327206, 28940506). ClinVar contains an entry for this variant (Variation ID: 375387). 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 FBXL4 protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
Pathogenic (Nov 04, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005326257.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024	Comment: Observed in homozygous or apparent homozygous state in patients with features of FBXL4-related mitochondrial DNA depletion syndrome in published literature and not observed in homozygous … (more) Observed in homozygous or apparent homozygous state in patients with features of FBXL4-related mitochondrial DNA depletion syndrome in published literature and not observed in homozygous state in controls (PMID: 28940506, 28327206); Published functional studies demonstrate a damaging effect, including impaired substrate ubiquitination via disrupting SCF-FBXL4 assembly (PMID: 36896912); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30804983, 28327206, 28940506, 36896912) (less)
Pathogenic (-)	no assertion criteria provided Method: research	Mitochondrial DNA depletion syndrome 13 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine Accession: SCV000494175.1 First in ClinVar: Feb 04, 2017 Last updated: Feb 04, 2017	Comment: This variant was identified in an individual with developmental delay, hypotonia, muscle weakness, autistic features, lactic acidosis.

Comment:

The NM_012160.4:c.419T>C (NP_036292.2:p.Val140Ala) [GRCH38: NC_000006.12:g.98926570A>G] variant in FBXL4 gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant meets one or more of the following evidence codes reported in the ACMG-guideline. 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. PP2:This is a missense variant in FBXL4 with a low rate of benign and high rate of pathogenic missense variations. PP3:Computational evidence/predictors indicate the variant has deleterious effect on FBXL4 structure, function, or protein-protein interaction. PP4:Patientâ€™s phenotype or family history is highly specific for FBXL4. Based on this evidence code ClinGen Pathogenicity Calculator (PMID:28081714) suggested that the variant is Likely Pathogenic.

Comment:

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 140 of the FBXL4 protein (p.Val140Ala). This variant is present in population databases (no rsID available, gnomAD 0.009%). This missense change has been observed in individuals with clinical features of mitochondrial DNA depletion syndrome (PMID: 28327206, 28940506). ClinVar contains an entry for this variant (Variation ID: 375387). 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 FBXL4 protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Comment:

Observed in homozygous or apparent homozygous state in patients with features of FBXL4-related mitochondrial DNA depletion syndrome in published literature and not observed in homozygous state in controls (PMID: 28940506, 28327206); Published functional studies demonstrate a damaging effect, including impaired substrate ubiquitination via disrupting SCF-FBXL4 assembly (PMID: 36896912); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30804983, 28327206, 28940506, 36896912)

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
Molecular and clinical spectra of FBXL4 deficiency.	El-Hattab AW	Human mutation	2017	PMID: 28940506
Lessons learned from additional research analyses of unsolved clinical exome cases.	Eldomery MK	Genome medicine	2017	PMID: 28327206

Text-mined citations for rs1057519447 ...

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 Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_001278716.2(FBXL4):c.419T>C (p.Val140Ala)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1057519447 ...