ClinVar Miner

Submissions for variant NM_001278716.2(FBXL4):c.1303C>T (p.Arg435Ter) (rs201889294)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000622490 SCV000740716 pathogenic Inborn genetic diseases 2014-08-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000604628 SCV000731341 pathogenic Mitochondrial DNA depletion syndrome 2016-12-23 criteria provided, single submitter clinical testing The p.Arg435X (NM_012160.4 c.1303C>T) variant in FBXL4 has been reported in 1 ho mozygous and 2 compound heterozygous individuals with clinical features of mitoc hondrial DNA depletion syndrome 13 (Bonnen 2013, Van Rij 2016, and Prionska 2016 ). This variant has been identified in 0.012% (1/8652) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSN P rs201889294). This nonsense variant leads to a premature termination codon at position 435, which is predicted to lead to a truncated or absent protein. In su mmary, the p.Arg435X variant meets criteria to be classified as pathogenic for m itochondrial DNA depletion syndrome in an autosomal recessive manner, based upon occurrence in patients and predicted functional impact.
OMIM RCV000056328 SCV000087497 pathogenic Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type) 2013-09-05 no assertion criteria provided literature only
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000056328 SCV000598187 pathogenic Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type) 2017-08-10 criteria provided, single submitter clinical testing The NM_012160.4:c.1303C>T (NP_036292.2:p.Arg435Ter) [GRCH38: NC_000006.12:g.98899282G>A] variant in FBXL4 gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:23993193 ; 27099744 . 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.

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