ClinVar Miner

Submissions for variant NM_139241.3(FGD4):c.1348A>G (p.Met450Val) (rs201186597)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235299 SCV000292932 uncertain significance not specified 2015-06-08 criteria provided, single submitter clinical testing The M450V variant has not been published as pathogenic, nor has it been reported as a benign polymorphism to our knowledge. It 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 M450V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and a missense variants in a nearby residue (R442H) has been reported in the Human Gene Mutation Database in association with Charcot-Marie-Tooth, type 4H (Stenson et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic or a rare benign variant.
Invitae RCV000559732 SCV000657978 uncertain significance Charcot-Marie-Tooth disease type 4 2020-08-02 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 450 of the FGD4 protein (p.Met450Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs201186597, ExAC 0.05%). This variant has not been reported in the literature in individuals with a FGD4-related disease. ClinVar contains an entry for this variant (Variation ID: 245800). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C1). In summary, this variant has uncertain impact on FGD4 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 5

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