ClinVar Miner

Submissions for variant NM_014845.5(FIG4):c.2567C>T (p.Ser856Leu) (rs200970494)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000197681 SCV000255005 uncertain significance Charcot-Marie-Tooth disease type 4 2018-03-09 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 856 of the FIG4 protein (p.Ser856Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs200970494, ExAC 0.001%). This variant has not been reported in the literature in individuals with FIG4-related disease. ClinVar contains an entry for this variant (Variation ID: 216681). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine 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.
GeneDx RCV000439703 SCV000533972 uncertain significance not provided 2016-12-27 criteria provided, single submitter clinical testing The S856L variant in the FIG4 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant was not observed at any significant frequency in approximately 6500 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 S856L 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. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret S856L as a variant of uncertain significance.

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