ClinVar Miner

Submissions for variant NM_001278716.2(FBXL4):c.1232G>A (p.Cys411Tyr) (rs773850151)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000499421 SCV000598162 likely pathogenic Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type) 2017-08-10 criteria provided, single submitter clinical testing The NM_012160.4:c.1232G>A (NP_036292.2:p.Cys411Tyr) [GRCH38: NC_000006.12:g.98899353C>T] variant in FBXL4 gene is interpretated to be a Likely 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. 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. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 13 in multiple affected family members. 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: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 Likely Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000499421 SCV000894400 likely pathogenic Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type) 2018-10-31 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV000499421 SCV001132568 likely pathogenic Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type) 2018-11-15 criteria provided, single submitter research The homozygous p.Cys411Tyr variant in FBXL4 was identified by our study in one individual with mitochondrial DNA depletion syndrome. This variant has been reported likely pathogenic in ClinVar by Baylor College of Medicine (ClinVar ID: 437475). This variant has been reported in the literature in the compound heterozygous state alongside a pathogenic variant, Arg435Gln, in two affected male individuals, and in the homozygous state in one affected male individual (Huemer et al. 2015; PMID: 25868664). This variant has also been reported in the literature in the compound heterozygous state alongside a different pathogenic variant, Cys547Ter, in an affected male proband (Dai et al. 2017; PMID: 27743463). This variant has been identified in <0.01% (3/24022) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs773850151). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.