ClinVar Miner

Submissions for variant NM_001278716.2(FBXL4):c.1304G>A (p.Arg435Gln) (rs754142863)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000623300 SCV000741866 pathogenic Inborn genetic diseases 2016-10-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
GeneDx RCV000493951 SCV000583275 likely pathogenic not provided 2017-05-30 criteria provided, single submitter clinical testing The R435Q variant in the FBXL4 gene has previously been reported in association with FBXL4-deficiency in two patients who were also heterozygous for a second missense variant in FBXL4 (Huemer et al., 2015). This variant has also been observed multiple times with a pathogenic variant in unrelated patients referred for genetic testing at GeneDx. The R435Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R435Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In summary, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000501572 SCV000598163 likely pathogenic Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type) 2017-08-10 criteria provided, single submitter clinical testing The NM_012160.4:c.1304G>A (NP_036292.2:p.Arg435Gln) [GRCH38: NC_000006.12:g.98899281C>T] variant in FBXL4 gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:25868664 . This variant meets one or more of the following evidence codes reported in the ACMG-guideline. 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. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 13 in multiple affected family members. PP2:This is a missense variant in FBXL4 with a low rate of benign and high rate of pathogenic missense variations. 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 Likely Pathogenic.

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