ClinVar Miner

Submissions for variant NM_139241.3(FGD4):c.50C>G (p.Pro17Arg) (rs371407163)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236575 SCV000293572 uncertain significance not provided 2018-01-02 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the FGD4 gene. The P17R variant has notbeen published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P17R variant is observed in 29/126,648 (0.02%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). The P17R 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. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rarebenign variant.
Invitae RCV000536689 SCV000657982 uncertain significance Charcot-Marie-Tooth disease type 4 2018-06-26 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 17 of the FGD4 protein (p.Pro17Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is present in population databases (rs371407163, ExAC 0.02%). This variant has not been reported in the literature in individuals with FGD4-related disease. ClinVar contains an entry for this variant (Variation ID: 246146). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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