ClinVar Miner

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

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Total submissions: 21
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000143812 SCV000278978 pathogenic not provided 2021-04-14 criteria provided, single submitter clinical testing Published functional studies demonstrate protein instability resulting in low levels of FIG4 protein (Lenk et al., 2011); Observed in the heterozygous state in multiple individuals with ALS or PLS (Cady et al., 2015; Osmanovic et al., 2017; Morgan et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30373780, 24878229, 23489662, 18261132, 20630877, 25617005, 22131434, 19118816, 17572665, 21705420, 21655088, 27549087, 28051077, 25382069, 28859335, 29468183, 32022442, 31980526, 32268254, 28430856, 31589614, 33096303, 32376792)
Weber Lab,Hannover Medical School RCV000416487 SCV000299294 pathogenic Amyotrophic lateral sclerosis type 11 2016-09-13 criteria provided, single submitter research
Invitae RCV000476702 SCV000546063 pathogenic Charcot-Marie-Tooth disease type 4 2020-10-27 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, Invitae). 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.
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
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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000143812 SCV001154843 pathogenic not provided 2020-07-01 criteria provided, single submitter clinical testing
Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University RCV001095515 SCV001251096 likely benign Amyotrophic lateral sclerosis 2020-03-31 criteria provided, single submitter research
Illumina Clinical Services Laboratory,Illumina RCV000416487 SCV001313896 likely benign Amyotrophic lateral sclerosis type 11 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001270162 SCV001366570 uncertain significance Yunis-Varon syndrome 2019-05-06 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PP3,BP1,BS1.
Johns Hopkins Genomics, Johns Hopkins University RCV000001791 SCV001430671 pathogenic Charcot-Marie-Tooth disease, type 4J 2020-07-17 criteria provided, single submitter clinical testing This FIG4 variant (rs121908287) is rare in a large population dataset (284/282242 total alleles; 0.1%; no homozygotes), and has an entry in ClinVar. Three bioinformatic tools queried predict that p.Ile41Thr would be damaging, and the isoleucine residue at this position is strongly conserved across the species assessed. Functional studies in proband fibroblasts, cultured cells, and yeast demonstrate that the p.Ile41Thr substitution leads to low levels of FIG4 protein. This variant is not predicted to affect normal exon 2 splicing, although this has not been confirmed experimentally to our knowledge. This variant in the FIG4 gene has been reported previously in association with CMT4J in individuals with a second FIG4 pathogenic variant on the opposite chromosome. A small number of patients with clinically diagnosed Charcot-Marie-Tooth disease (0.45%) are heterozygous carriers of the c.122T>C variant; some of these patients might carry an undetected non-coding variant that was missed by exon sequencing. We consider c.122T>C to be pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000143812 SCV001447036 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Baylor Genetics RCV001330564 SCV001522281 pathogenic Polymicrogyria, bilateral temporooccipital 2019-09-30 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as pathogenic [PMID: 28051077, 28859335, 28430856, 18261132, 25617005, 21655088, 24878229, 17572665, 20630877, 23489662, 27549087, ClinVar ID: 1721]
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000001791 SCV001653109 pathogenic Charcot-Marie-Tooth disease, type 4J 2020-06-19 criteria provided, single submitter clinical testing The p.Ile41Thr variant in FIG4 has been reported in at least 23 individuals with Charcot Marie Tooth type 4J and segregated with disease in at least 14 affected individuals (first reported by Chow 2007 PMID: 17572665; >15 publications including de Leeuw 2008 PMID: 18261132, Ikonomov 2010 PMID: 20630877, Lenk 2011 PMID: 21655088, Cottenie 2013 PMID: 23489662, Lassuthova 2016 PMID: 27549087, Gentil 2017 PMID: 28859335, Morgan 2017 PMID: 28430856, Bacquet 2018 PMID: 30373780, Orengo 2018 PMID: 29468183). It has also been identified in 0.189% (244/128994) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar as pathogenic by multiple submitters (Variation ID 1721). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro and in vivo functional studies both provide some evidence that this variant impacts protein function (first by de Leeuw 2008 PMID: 18261132) and animal models in mice have shown that this variant causes peripheral neuropathy (Gentil 2017: 28859335). This variant was observed in trans with >10 different nonsense variants in FIG4, which are classified as pathogenic by other laboratories. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive CMT4J. ACMG/AMP Criteria applied: PM3_VeryStrong, PS3_Moderate, PP3, PP1_Strong.
Mayo Clinic Laboratories, Mayo Clinic RCV000143812 SCV001714176 pathogenic not provided 2021-01-04 criteria provided, single submitter clinical testing
OMIM RCV000001791 SCV000021947 pathogenic Charcot-Marie-Tooth disease, type 4J 2011-07-01 no assertion criteria provided literature only
GeneReviews RCV000001791 SCV000054640 pathologic Charcot-Marie-Tooth disease, type 4J 2012-09-13 no assertion criteria provided curation Converted during submission to Pathogenic.
Northcott Neuroscience Laboratory, ANZAC Research Institute RCV000143812 SCV000188705 non-pathogenic not provided no assertion criteria provided not provided Converted during submission to Benign.
GenomeConnect - Invitae Patient Insights Network RCV001535566 SCV001749552 not provided Charcot-Marie-Tooth disease, type 4J; Yunis-Varon syndrome no assertion provided phenotyping only Variant interpreted as Pathogenic and reported on 07-09-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Clinical Genetics,Academic Medical Center RCV000143812 SCV001922623 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000143812 SCV001957862 pathogenic not provided no assertion criteria provided clinical testing

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