ClinVar Miner

Submissions for variant NM_001278716.2(FBXL4):c.1444C>T (p.Arg482Trp) (rs398123061)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224233 SCV000280648 likely pathogenic not provided 2014-07-30 criteria provided, single submitter clinical testing
GeneDx RCV000224233 SCV000583379 pathogenic not provided 2017-05-31 criteria provided, single submitter clinical testing The R482W variant in the FBXL4 gene has been reported previously in association with encephalomyopathic mitochondrial DNA depletion syndrome, when present in the homozygous state or in the presence of a second FBXL4 variant (Gai et al., 2013; Dai et al., 2016). The R482W variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R482W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R482W as a pathogenic variant.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000056330 SCV000598168 likely pathogenic Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type) 2017-08-10 criteria provided, single submitter clinical testing The NM_012160.4:c.1444C>T (NP_036292.2:p.Arg482Trp) [GRCH38: NC_000006.12:g.98875673G>A] 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. 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.
Institute of Human Genetics,Klinikum rechts der Isar RCV000056330 SCV001430104 pathogenic Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type) 2019-10-04 criteria provided, single submitter clinical testing
OMIM RCV000056330 SCV000087499 pathogenic Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type) 2013-09-05 no assertion criteria provided literature only
Developmental Genetics Unit,King Faisal Specialist Hospital & Research Centre RCV000162170 SCV000196456 likely pathogenic Mitochondrial encephalomyopathy; Global developmental delay 2014-12-01 no assertion criteria provided research

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