ClinVar Miner

Submissions for variant NM_001278716.2(FBXL4):c.618_621dup (p.Glu208fs)

dbSNP: rs886041625
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000298072 SCV000330325 pathogenic not provided 2018-12-07 criteria provided, single submitter clinical testing The c.618_621dupACTG pathogenic variant in the FBXL4 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.618_621dupACTG variant causes a frameshift starting with codon Glutamic acid 208, changes this amino acid to a Threonine residue, and creates a premature Stop codon at position 5 of the new reading frame, denoted p.Glu208ThrfsX5. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.618_621dupACTG variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.618_621dupACTG as a pathogenic variant.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000502064 SCV000598192 pathogenic Mitochondrial DNA depletion syndrome 13 2017-08-10 criteria provided, single submitter clinical testing The NM_012160.4:c.618_621dup (NP_036292.2:p.Glu208ThrfsTer5) [GRCH38: NC_000006.12:g.98917612_98917615dup] variant in FBXL4 gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). 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. 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.
Invitae RCV000298072 SCV004294641 pathogenic not provided 2023-06-03 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 280414). This premature translational stop signal has been observed in individual(s) with clinical features of FBXL4-related conditions (PMID: 28940506, 32445240). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu208Thrfs*5) in the FBXL4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FBXL4 are known to be pathogenic (PMID: 23993193, 23993194, 25868664).

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