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

gnomAD frequency: 0.00005  dbSNP: rs200440128

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV000191084	SCV000245480	pathogenic	Mitochondrial DNA depletion syndrome 13	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.
Eurofins Ntd Llc (ga)	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	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	2022-05-18	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27290639, 27743463, 28940506, 26633545, 30804983, 32525278, 33726816)
Department of Molecular and Human Genetics, Baylor College of Medicine	RCV000191084	SCV001334104	pathogenic	Mitochondrial DNA depletion syndrome 13	2020-04-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001267292	SCV001445473	pathogenic	Inborn genetic diseases	2018-05-24	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000578719	SCV002064325	pathogenic	not provided	2017-08-29	criteria provided, single submitter	clinical testing
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	RCV000191084	SCV002102904	likely pathogenic	Mitochondrial DNA depletion syndrome 13	2021-01-28	criteria provided, single submitter	clinical testing
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV002273980	SCV002559092	pathogenic	Neurodevelopmental delay		criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000191084	SCV002793830	pathogenic	Mitochondrial DNA depletion syndrome 13	2022-03-23	criteria provided, single submitter	clinical testing
Invitae	RCV000578719	SCV003439479	pathogenic	not provided	2023-12-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg22*) 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). This variant is present in population databases (rs200440128, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with clinical features of FBXL4-related conditions (PMID: 27290639, 27743463). ClinVar contains an entry for this variant (Variation ID: 209153). For these reasons, this variant has been classified as Pathogenic.
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