ClinVar Miner

Submissions for variant NM_001278716.2(FBXL4):c.616C>T (p.Arg206Ter)

gnomAD frequency: 0.00001  dbSNP: rs964532159
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Total submissions: 3
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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 RCV000499561 SCV000598185 pathogenic Mitochondrial DNA depletion syndrome 13 2017-08-10 criteria provided, single submitter clinical testing The NM_012160.4:c.616C>T (NP_036292.2:p.Arg206Ter) [GRCH38: NC_000006.12:g.98917616G>A] 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. Based on this evidence code ClinGen Pathogenicity Calculator (PMID:28081714) suggested that the variant is Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000499561 SCV002805606 likely pathogenic Mitochondrial DNA depletion syndrome 13 2022-03-30 criteria provided, single submitter clinical testing
Ambry Genetics RCV005338208 SCV006004562 pathogenic Inborn genetic diseases 2025-01-09 criteria provided, single submitter clinical testing The c.616C>T (p.R206*) alteration, located in exon 4 (coding exon 2) of the FBXL4 gene, consists of a C to T substitution at nucleotide position 616. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 206. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.006% (2/31402) total alleles studied. The highest observed frequency was 0.023% (2/8712) of African alleles. This variant has been identified in the homozygous state in multiple individuals with clinical features consistent with FBXL4-related mitochondrial DNA depletion syndrome (El-Hattab, 2017; Trujillano, 2017). Based on the available evidence, this alteration is classified as pathogenic.

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