ClinVar Miner

Submissions for variant NM_014845.5(FIG4):c.2459+1G>A (rs747768373)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236022 SCV000293534 pathogenic not provided 2015-11-24 criteria provided, single submitter clinical testing The c.2459+1G>A variant in the FIG4 gene has been reported previously in one individual referred for CMT genetic testing (DiVincenzo et al., 2014). This splice site variant destroys the canonical splice donor site in intron 21. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.2459+1G>A variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.2459+1G>A as a pathogenic variant.
Ambry Genetics RCV000622554 SCV000740819 likely pathogenic Inborn genetic diseases 2015-01-21 criteria provided, single submitter clinical testing
Invitae RCV001243544 SCV001416712 pathogenic Charcot-Marie-Tooth disease type 4 2019-11-11 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 21 of the FIG4 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs747768373, ExAC 0.01%). This variant has been observed in individual(s) with clinical features of Charcot-Marie-Tooth disease (PMID: 30740813). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 246120). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 30740813). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and 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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