ClinVar Miner

Submissions for variant NM_001278716.2(FBXL4):c.1067del (p.Gly356fs) (rs1554219474)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000504121 SCV000598193 pathogenic Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type) 2017-08-10 criteria provided, single submitter clinical testing The NM_012160.4:c.1067del (NP_036292.2:p.Gly356AlafsTer15) [GRCH38: NC_000006.12:g.98905463del] variant in FBXL4 gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:23993194 ; 25868664 . 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. Based on this evidence code ClinGen Pathogenicity Calculator (PMID:28081714) suggested that the variant is Pathogenic.
GeneDx RCV000657172 SCV000778893 pathogenic not provided 2018-05-21 criteria provided, single submitter clinical testing The c.1067delG variant has been reported previously in the homozygous and compound heterozygous states in patients with symptoms that include early-onset lactic acidemia, hypotonia, encephalopathy, developmental delay, failure to thrive, microcephaly and defects in the respiratory chain (Gai et al. 2013; Huemer et al. 2015; Al-Shamsi et al. 2016). The c.1067delG variant is not observed in large population cohorts (Lek et al., 2016). The c.1067delG variant causes a frameshift starting with codon Glycine 356, changes this amino acid to an Alanine residue and creates a premature Stop codon at position 15 of the new reading frame, denoted p.Gly356AlafsX15. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we interpret this variant as pathogenic.
Baylor Genetics RCV000504121 SCV000807421 pathogenic Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type) 2017-09-01 criteria provided, single submitter clinical testing This mutation has been previously reported as disease-causing and was found twice in our laboratory: once in trans with another pathogenic variant in an 8-year-old female with primary mitochondrial respiratory chain disease; once homozygous in a 3-year-old male with regression, severe failure to thrive, hypotonia, microcephaly, severe lactic acidosis, nystagmus, mild dysmorphisms, and 3 siblings who died in infancy
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000657172 SCV000802753 likely pathogenic not provided 2016-03-08 no assertion criteria provided clinical testing

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