ClinVar Miner

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
Invitae RCV000553432 SCV000657846 uncertain significance Charcot-Marie-Tooth disease type 4 2019-11-05 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.
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.

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