Submissions for variant NM_014845.5(FIG4):c.101C>T (p.Thr34Met) (rs375691683)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756166	SCV000883892	uncertain significance	not provided	2017-11-21	criteria provided, single submitter	clinical testing	The p.Thr34Met variant (rs375691683) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.01 percent (identified on 27 out of 276,426 chromosomes).The threonine at position 34 is highly conserved considering 12 species (Alamut v2.10) and computational analyses of the effects of the p.Thr34Met variant on protein structure and function indicate a deleterious effect (SIFT: damaging, MutationTaster: disease causing, PolyPhen-2: probably damaging). Altogether, there is not enough evidence to classify the p.Thr34Met variant with certainty.
Invitae	RCV000553432	SCV000657846	uncertain significance	Charcot-Marie-Tooth disease type 4	2018-08-21	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with methionine at codon 34 of the FIG4 protein (p.Thr34Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs375691683, ExAC 0.02%). 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 do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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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