ClinVar Miner

Submissions for variant NM_139241.3(FGD4):c.893T>G (p.Met298Arg) (rs63749871)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000695680 SCV000824194 pathogenic Charcot-Marie-Tooth disease type 4 2019-02-22 criteria provided, single submitter clinical testing This sequence change replaces methionine with arginine at codon 298 of the FGD4 protein (p.Met298Arg). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with Charcot-Marie-Tooth disease, type 4 in a family (PMID: 17564959) and has been observed in individuals affected with Charcot-Marie-Tooth disease (PMID: 17564972, Invitae). ClinVar contains an entry for this variant (Variation ID: 38445). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Experimental studies in patient fibroblasts and peripheral nerve cells have shown that this missense change results in transcripts that are abnormally spliced (PMID: 17564959). For these reasons, this variant has been classified as Pathogenic.
GeneReviews RCV000032001 SCV000054710 pathologic Charcot-Marie-Tooth disease, type 4H 2012-09-13 no assertion criteria provided curation Converted during submission to Pathogenic.
Inherited Neuropathy Consortium RCV000789104 SCV000928455 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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