ClinVar Miner

Submissions for variant NM_014845.6(FIG4):c.2433AGA[2] (p.Glu813del) (rs876661144)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000216486 SCV000279661 uncertain significance not provided 2015-12-17 criteria provided, single submitter clinical testing The c.2439_2441delAGA variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.2439_2441delAGA variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The c.2439_2441delAGA variant results in an in-frame deletion of a single Glutamic acid residue, denoted p.E813del. However, this deletion occurs at a position that is not conserved. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Broad Institute Rare Disease Group, Broad Institute RCV001254717 SCV001430790 likely pathogenic Cerebral hypomyelination 2020-05-28 criteria provided, single submitter research The heterozygous p.Glu813del variant in FIG4 was identified by our study, in the compound heterozygous state, along with another likely pathogenic variant, in 3 siblings with cerebral hypomyelination (PMID: 30740813). This variant has also been reported as a VUS by GeneDx in ClinVar (Variation ID: 234659). This variant has been identified in 0.003% (1/34550) of Latino chromosomes and 0.002% (2/113662) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs876661144). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the p.Glu813del variant may slightly impact protein function (PMID: 30740813). However, these types of assays may not accurately represent biological function. This variant is a deletion of 1 amino acid at position 813 and is not predicted to alter the protein reading-frame. It is unclear if this deletion will impact the protein. The presence of this variant in combination with a likely pathogenic variant and in 3 siblings with cerebral hypomyelination increases the likelihood that the p.Glu813del variant is pathogenic (PMID: 30740813). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM3, PM4_Supporting, PP1, PS3_Supporting (Richards 2015).

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