Submissions for variant NM_014845.5(FIG4):c.2405A>G (p.Tyr802Cys) (rs370293982)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236910	SCV000293023	uncertain significance	not provided	2015-08-06	criteria provided, single submitter	clinical testing	The Y802C 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 Y802C 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. However, missense variants in nearby residues have not been been reported in Human Gene Mutation Database in association with FIG4-related disorders (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic or a rare benign variant.
Invitae	RCV001203773	SCV001374949	uncertain significance	Charcot-Marie-Tooth disease type 4	2019-09-25	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine with cysteine at codon 802 of the FIG4 protein (p.Tyr802Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs370293982, ExAC 0.002%). This variant has not been reported in the literature in individuals with FIG4-related conditions. ClinVar contains an entry for this variant (Variation ID: 245855). 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. 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.