ClinVar Miner

Submissions for variant NM_014845.5(FIG4):c.122T>C (p.Ile41Thr) (rs121908287)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000507425 SCV000603714 pathogenic not specified 2016-07-07 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000143812 SCV000613294 pathogenic not provided 2016-03-07 criteria provided, single submitter clinical testing
GeneDx RCV000143812 SCV000278978 pathogenic not provided 2018-11-01 criteria provided, single submitter clinical testing The I41T pathogenic variant in the FIG4 gene has been reported previously in association with Charcot-Marie-Tooth disease type 4J (CMT4J) in individuals with a second FIG4 pathogenic variant on the other allele (Chow et al., 2007; Cottenie et al., 2013; Menezes et al., 2014). Functional studies have shown that the I41T mutant protein is unstable, resulting in low levels of FIG4 protein (Lenk et al., 2011). Additionally, this pathogenic variant is a non-conservative amino acid substitution at a position that is conserved across species. The I41T variant is observed in 239/126,554 (0.2%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). Therefore, we interpreted I41T as a pathogenic variant.
GeneReviews RCV000001791 SCV000054640 pathologic Charcot-Marie-Tooth disease, type 4J 2012-09-13 no assertion criteria provided curation Converted during submission to Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000001791 SCV000916118 pathogenic Charcot-Marie-Tooth disease, type 4J 2018-10-25 criteria provided, single submitter clinical testing The FIG4 c.122T>C (p.Ile41Thr) missense variant has been reported in four studies in which it is found in a total of 36 individuals with Charcot-Marie-Tooth, type 4, including in 18 in a compound heterozygous state, all in combination with a null variant, and in 18 in a heterozygous state in whom the second variant has not been found (Chow et al. 2007; Nicholson et al. 2011; Cottenie et al. 2013; Menezes et al. 2014). The p.Ile41Thr variant was found in 13 of 6064 controls, and is reported at a frequency of 0.001889 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies in proband fibroblasts, cultured cells, and yeast demonstrated that the p.Ile41Thr variant leads to low levels of protein due to impaired interaction with the scaffold protein, VAC14, which stabilizes FIG4 and impairs kinase activation (Chow et al. 2007; Zhang et al. 2008; Ikonomov et al. 2010; Lenk et al. 2011). In a mouse model, overexpression (5-fold) of variant p.Ile41Thr in Fig4-null mice rescued the severe neurodegenerative phenotype and lethality, whereas lesser overexpression (2-fold) resulted in partial rescue and a CMT-like phenotype (Lenk et al. 2011). Based on the collective evidence, the p.Ile41Thr variant is classified as pathogenic for Charcot-Marie-Tooth, type 4. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000476702 SCV000546063 pathogenic Charcot-Marie-Tooth disease type 4 2018-12-14 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 41 of the FIG4 protein (p.Ile41Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs121908287, ExAC 0.2%). This variant has been observed on the opposite chromosome (in trans) from loss-of-function variants in many individuals affected with Charcot-Marie-Tooth disease type 4 (PMID: 17572665, 23489662, 21705420, 24878229, 18556664). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 1721). Multiple experimental studies have shown that this missense change is deleterious (PMID: 17572665, 20630877, 21655088). For these reasons, this variant has been classified as Pathogenic.
Northcott Neuroscience Laboratory, ANZAC Research Institute RCV000143812 SCV000188705 non-pathogenic not provided no assertion criteria provided not provided Converted during submission to Benign.
OMIM RCV000001791 SCV000021947 pathogenic Charcot-Marie-Tooth disease, type 4J 2011-07-01 no assertion criteria provided literature only
Weber Lab,Hannover Medical School RCV000416487 SCV000299294 pathogenic Amyotrophic lateral sclerosis type 11 2016-09-13 criteria provided, single submitter research

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