ClinVar Miner

Submissions for variant NM_139241.3(FGD4):c.1711C>G (p.Pro571Ala) (rs144693221)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236629 SCV000293770 uncertain significance not provided 2016-01-06 criteria provided, single submitter clinical testing The P571A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant 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 P571A 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 and Alanine is observed at this position in other species. In silico analysis predicts this variant likely does not alter 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.
Illumina Clinical Services Laboratory,Illumina RCV000263275 SCV000378193 uncertain significance Charcot-Marie-Tooth disease type 4 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000263275 SCV000813636 uncertain significance Charcot-Marie-Tooth disease type 4 2018-10-09 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 571 of the FGD4 protein (p.Pro571Ala). The proline residue is weakly conserved and there is a small physicochemical difference between proline and alanine. This variant is present in population databases (rs144693221, ExAC 0.07%). This variant has not been reported in the literature in individuals with FGD4-related disease. ClinVar contains an entry for this variant (Variation ID: 246288). 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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