VCV000066092.4 - ClinVar

NM_001278716.2(FBXL4):c.1703G>C (p.Gly568Ala)

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.

(4)

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.1703G>C (p.Gly568Ala)

Variation ID: 66092 Accession: VCV000066092.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6q16.1 6: 98874441 (GRCh38) [ NCBI UCSC ] 6: 99322317 (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 20, 2013	Jul 22, 2023	Nov 16, 2017

HGVS

Nucleotide	Protein	Molecular consequence
NM_001278716.2:c.1703G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001265645.1:p.Gly568Ala	missense
NM_012160.5:c.1703G>C	NP_036292.2:p.Gly568Ala	missense
NR_103836.2:n.1688G>C		non-coding transcript variant
NC_000006.12:g.98874441C>G
NC_000006.11:g.99322317C>G
NG_033903.1:g.78566G>C
	Q9UKA2:p.Gly568Ala

... more HGVS ... less HGVS

Protein change

G568A

Other names

Canonical SPDI

NC_000006.12:98874440:C: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.

Links

ClinGen: CA144889 UniProtKB: Q9UKA2#VAR_070862 OMIM: 605654.0003 dbSNP: rs398123060 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	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Nov 16, 2017	RCV000056329.10

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: SCV000598175.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015	Publications: PubMed (3) PubMed: 23993194‚ 25868664‚ 27743463 Comment: The NM_012160.4:c.1703G>C (NP_036292.2:p.Gly568Ala) [GRCH38: NC_000006.12:g.98874441C>G] variant in FBXL4 gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has … (more) The NM_012160.4:c.1703G>C (NP_036292.2:p.Gly568Ala) [GRCH38: NC_000006.12:g.98874441C>G] variant in FBXL4 gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:23993194 ; 25868664 ; 27743463 . 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. 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 Likely Pathogenic. (less)
Pathogenic (Nov 16, 2017)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Mitochondrial DNA depletion syndrome 13 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV000680231.1 First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018	Sex: female Tissue: blood
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mitochondrial DNA depletion syndrome 13 Affected status: yes Allele origin: unknown	3billion Accession: SCV004013850.1 First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023	Publications: PubMed (3) PubMed: 25868664‚ 27743463‚ 23993194 Comment: The missense variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene … (more) The missense variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.52; 3Cnet: 0.96). The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000066092/PMID: 23993194). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 23993194, 25868664, 27743463). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Abnormal periventricular white matter morphology (present) , Cognitive impairment (present) , Delayed speech and language development (present) , Global developmental delay (present) , Intellectual disability … (more) Abnormal periventricular white matter morphology (present) , Cognitive impairment (present) , Delayed speech and language development (present) , Global developmental delay (present) , Intellectual disability (present) , Seizure (present) , Spasticity (present) , Abnormality of the nervous system (present) , Hyperammonemia (present) , Hypoglycemia (present) , Lactic acidosis (present) (less)
Pathogenic (Sep 05, 2013)	no assertion criteria provided Method: literature only	MITOCHONDRIAL DNA DEPLETION SYNDROME 13 (ENCEPHALOMYOPATHIC TYPE) Affected status: not provided Allele origin: germline	OMIM Accession: SCV000087498.1 First in ClinVar: Oct 20, 2013 Last updated: Oct 20, 2013	Publications: PubMed (1) PubMed: 23993194 Comment on evidence: In a 4-year-old boy, born of consanguineous Saudi Arabian parents, with MTDPS13 (615471), Gai et al. (2013) identified a homozygous c.1703G-C transversion in the FBXL4 … (more) In a 4-year-old boy, born of consanguineous Saudi Arabian parents, with MTDPS13 (615471), Gai et al. (2013) identified a homozygous c.1703G-C transversion in the FBXL4 gene, resulting in a gly568-to-ala (G568A) substitution at a highly conserved residue in the LRR domain. The mutation was found by homozygosity mapping followed by whole-exome sequencing. The mutation was not present in 242 Saudi exomes, in 4,500 in-house European control chromosomes, or in the Exome Variant Server database. (less)

Comment:

The NM_012160.4:c.1703G>C (NP_036292.2:p.Gly568Ala) [GRCH38: NC_000006.12:g.98874441C>G] variant in FBXL4 gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:23993194 ; 25868664 ; 27743463 . 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. 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 Likely Pathogenic.

Comment:

The missense variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.52; 3Cnet: 0.96). The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000066092/PMID: 23993194). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 23993194, 25868664, 27743463). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.

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
FBXL4 defects are common in patients with congenital lactic acidemia and encephalomyopathic mitochondrial DNA depletion syndrome.	Dai H	Clinical genetics	2017	PMID: 27743463
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

Text-mined citations for rs398123060 ...

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 Jun 23, 2024

ClinVar Genomic variation as it relates to human health

NM_001278716.2(FBXL4):c.1703G>C (p.Gly568Ala)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs398123060 ...