ClinVar Miner

Submissions for variant NM_139241.3(FGD4):c.569T>A (p.Leu190Gln) (rs144980336)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236923 SCV000293026 uncertain significance not provided 2015-08-05 criteria provided, single submitter clinical testing The L190Q variant has not been published as pathogenic, nor has it been reported as a benign polymorphism to our knowledge. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The L190Q 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. However, this substitution occurs at a position that is not conserved across species. 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 or a rare benign variant.
Invitae RCV000654106 SCV000775996 uncertain significance Charcot-Marie-Tooth disease type 4 2017-10-10 criteria provided, single submitter clinical testing This sequence change replaces leucine with glutamine at codon 190 of the FGD4 protein (p.Leu190Gln). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and glutamine. This variant is present in population databases (rs144980336, 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: 245858). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine 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, 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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