ClinVar Miner

Submissions for variant NM_014845.5(FIG4):c.1373dup (p.Leu458fs) (rs770043095)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486299 SCV000567433 pathogenic not provided 2018-06-21 criteria provided, single submitter clinical testing The c.1373dupT duplication has been reported previously in two unrelated patients with early onset Charcot-Marie-Tooth disease type 4J (CMT4J) who also have the I41T variant on the opposite allele (Nicholson et al., 2011). The duplication causes a frameshift starting with codon Leucine 458, changes this amino acid to a Phenylalanine residue and creates a premature Stop codon at position 5 of the new reading frame, denoted p.Leu458PhefsX5. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, we interpret c.1373dupT as a pathogenic variant.
Invitae RCV000801106 SCV000940865 pathogenic Charcot-Marie-Tooth disease type 4 2019-12-13 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu458Phefs*5) in the FIG4 gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed on the opposite chromosome (in trans) from another pathogenic variant in an individual affected with autosomal recessive Charcot-Marie-Tooth disease (PMID: 21705420). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant is also known as c.1370insT in the literature. ClinVar contains an entry for this variant (Variation ID: 419553). Loss-of-function variants in FIG4 are known to be pathogenic (PMID: 23623387). For these reasons, this variant has been classified as Pathogenic.
Inherited Neuropathy Consortium RCV000789120 SCV000928471 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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