ClinVar Miner

Submissions for variant NM_139241.3(FGD4):c.1562A>G (p.Asp521Gly) (rs141237776)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224105 SCV000281041 uncertain significance not provided 2016-01-21 criteria provided, single submitter clinical testing Converted during submission to Uncertain significance.
GeneDx RCV000224105 SCV000292880 uncertain significance not provided 2017-01-06 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the FGD4 gene. The D521G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The D521G variant is observed in 9/66,728 (0.01%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D521G 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 analysis predicts this variant is probably damaging to the protein structure/function. However, this substitution occurs at a position that is not conserved. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000654083 SCV000775973 uncertain significance Charcot-Marie-Tooth disease type 4 2018-11-28 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 521 of the FGD4 protein (p.Asp521Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs141237776, ExAC 0.01%). This variant has not been reported in the literature in individuals with FGD4-related disease. ClinVar contains an entry for this variant (Variation ID: 235447). 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 C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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