ClinVar Miner

Submissions for variant NM_001278716.2(FBXL4):c.1025C>G (p.Ser342Cys) (rs780707718)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413651 SCV000491727 uncertain significance not specified 2016-11-28 criteria provided, single submitter clinical testing The S342C variant in the FBXL4 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The S342C 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. The S342C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret S342C as a variant of uncertain significance.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000500631 SCV000598380 uncertain significance Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type) 2017-08-10 criteria provided, single submitter reference population The NM_012160.4:c.1025C>G (NP_036292.2:p.Ser342Cys) [GRCH38: NC_000006.12:g.98905504G>C] variant in FBXL4 gene is interpretated to be a Uncertain Significance - Conflicting Evidence based on ACMG guidelines (PMID: 25741868). 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. BP4:Computational evidence/predictors indicate no impact on the FBXL4 structure, function, or protein-protein interaction. Based on this evidence code ClinGen Pathogenicity Calculator (PMID:28081714) suggested that the variant is Uncertain Significance - Conflicting Evidence.

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