ClinVar Miner

Submissions for variant NM_139241.3(FGD4):c.329T>C (p.Leu110Pro) (rs142609007)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000233379 SCV000291963 uncertain significance not provided 2018-07-23 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the FGD4 gene. The L110P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The L110P variant is observed in 35/66728 (0.05%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L110P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved. 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 variant or a rare benign variant.
Invitae RCV000558088 SCV000657981 uncertain significance Charcot-Marie-Tooth disease type 4 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 110 of the FGD4 protein (p.Leu110Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. This variant is present in population databases (rs142609007, ExAC 0.05%). This variant has not been reported in the literature in individuals with an FGD4-related disease. ClinVar contains an entry for this variant (Variation ID: 242314). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The proline amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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