ClinVar Miner

Submissions for variant NM_001278716.2(FBXL4):c.1294G>A (p.Val432Ile)

gnomAD frequency: 0.00001  dbSNP: rs760332582
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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 RCV000503016 SCV000598430 uncertain significance Mitochondrial DNA depletion syndrome 13 2017-08-10 criteria provided, single submitter reference population The NM_012160.4:c.1294G>A (NP_036292.2:p.Val432Ile) [GRCH38: NC_000006.12:g.98899291C>T] 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.
GeneDx RCV001824324 SCV002073986 uncertain significance not provided 2024-02-09 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp RCV001824324 SCV002140635 uncertain significance not provided 2022-10-28 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FBXL4 protein function. ClinVar contains an entry for this variant (Variation ID: 437726). This variant has not been reported in the literature in individuals affected with FBXL4-related conditions. This variant is present in population databases (rs760332582, gnomAD 0.006%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 432 of the FBXL4 protein (p.Val432Ile).

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