ClinVar Miner

Submissions for variant NM_014845.5(FIG4):c.737G>A (p.Trp246Ter) (rs776005417)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478168 SCV000568790 likely pathogenic not provided 2017-03-22 criteria provided, single submitter clinical testing A variant that is likely pathogenic has been identified in the FIG4 gene. The W246X nonsense variant has been reported previously in a cohort of individuals undergoing testing for Charcot-Marie-Tooth disease, but no further clinical or segregation information was provided (DiVincenzo et al., 2014). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Furthermore, the W246X variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Fulgent Genetics,Fulgent Genetics RCV000763552 SCV000894369 pathogenic Amyotrophic lateral sclerosis type 11; Polymicrogyria, bilateral temporooccipital; Charcot-Marie-Tooth disease, type 4J; Yunis-Varon syndrome 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV001232367 SCV001404923 pathogenic Charcot-Marie-Tooth disease type 4 2019-08-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp246*) in the FIG4 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant was reported in an individual who was referred for genetic testing for Charcot-Marie-Tooth disease (PMID: 25614874). ClinVar contains an entry for this variant (Variation ID: 420149). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in FIG4 are known to be pathogenic (PMID: 23623387). For these reasons, this variant has been classified as Pathogenic.

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