ClinVar Miner

Submissions for variant NM_014845.5(FIG4):c.1348C>T (p.Arg450Cys) (rs201072058)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000654072 SCV000775962 uncertain significance Charcot-Marie-Tooth disease type 4 2018-07-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 450 of the FIG4 protein (p.Arg450Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs201072058, ExAC 0.03%). This variant has not been reported in the literature in individuals with FIG4-related disease. 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000756165 SCV000883891 uncertain significance not provided 2017-10-03 criteria provided, single submitter clinical testing The p.Arg450Cys variant (rs201072058) has been reported in the medical literature in the heterozygous state in a single individual with Charcot-Marie-Tooth disease; however, no other FIG4 variants were identified in this individual so it is unclear if this variant contributed to disease (Nicholson 2011). The p.Arg450Cys variant is also listed in the Genome Aggregation Database (gnomAD) browser with an overall allele frequency of 0.0058% (identified in 16 out of 277,094 chromosomes). The arginine at codon 450 is moderately conserved considering 12 species (Alamut software v2.10.0), and computational analyses predict conflicting effects of this variant on protein structure/function (SIFT: tolerated, PolyPhen2: benign, MutationTaster: disease causing). Therefore, based on the available information, the clinical significance of the p.Arg450Cys variant cannot be determined with certainty.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.