ClinVar Miner

Submissions for variant NM_001278716.2(FBXL4):c.64C>T (p.Arg22Ter) (rs200440128)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000191084 SCV000245480 pathogenic Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type) 2014-01-27 criteria provided, single submitter clinical testing This nonsense variant is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found once in our laboratory homozygous in a 32-year-old male with intellectual disability, hypotonia, dragging of right foot when walking, tremors, dysmorphisms, hyperextensibility, failure to thrive, amblyopia, myopia, mitral valve prolapse, scoliosis, serial episodes of lactic acidosis, white matter abnormalities. Variant pathogenic in recessive state; heterozygotes are carriers.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000578719 SCV000339107 pathogenic not provided 2016-02-02 criteria provided, single submitter clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000191084 SCV000598180 pathogenic Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type) 2017-08-10 criteria provided, single submitter clinical testing The NM_012160.4:c.64C>T (NP_036292.2:p.Arg22Ter) [GRCH38: NC_000006.12:g.98926925G>A] variant in FBXL4 gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:27743463 ; 27290639 . 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: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 Pathogenic.
GeneDx RCV000578719 SCV000680951 pathogenic not provided 2017-11-07 criteria provided, single submitter clinical testing The R22X variant in the FBXL4 gene has been reported previously as both compound heterozygous and homozyogous in at least three individuals with features of mitochondrial disorders including congenital lactic acidemia, dysmorphic features, developmental delay, psychomotor retardation, hypotonia, seizures, hearing loss, leukodystrophy, tremor, and abnormal gait (Dai et al., 2016; Pronicka et al., 2016). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R22X variant is observed in 12/126378 alleles (0.0095%) from individuals of non-Finnish European background in large population cohorts (Lek et al., 2016)] We interpret R22X as a pathogenic variant.
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes RCV000578719 SCV000778274 pathogenic not provided 2017-07-27 no assertion criteria provided clinical testing

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