Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Broad Center for Mendelian Genomics, |
RCV001009605 | SCV001167358 | uncertain significance | Global developmental delay; Leukoencephalopathy; Developmental regression | 2020-03-09 | criteria provided, single submitter | research | The heterozygous c.1382C>G (p.Ser461Cys) variant in EIF2AK2 was identified by our study in 1 individual with developmental regression, leukoencephalopathy, and global developmental delay. Trio exome analysis showed this variant to be de novo with confirmed paternity and maternity. The c.1382C>G (p.Ser461Cys) variant in EIF2AK2 has not been previously reported in individuals with developmental regression, leukoencephalopathy, and global developmental delay and this variant was absent from large population studies. The EIF2AK2 gene has no established gene-disease association. However, this gene has a role in the EIF2B pathway, which has been associated with vanishing white matter leukoencephalopathies. Unpublished cohort data has identified other unrelated patients with similar neurologic phenotypes and suggest that de novo missense variants are implicated in disease. Functional studies demonstrate this variant impairs kinase activity of EIF2AK2 (publication pending). It is of note that computational prediction tools, including splice predictors, suggest that this variant may not impact the protein. Additionally, the serine (Ser) at position 461 is not highly conserved in mammals and evolutionary distant species, and 2 mammals (dolphins and killer whales) carry a cystine (Cys), raising the possibility that this change at this position may be tolerated. In summary, the clinical significance of the Ser461Cys variant is uncertain. |
| SIB Swiss Institute of Bioinformatics | RCV001093624 | SCV001468566 | uncertain significance | Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome | 2020-12-18 | criteria provided, single submitter | curation | This variant is interpreted as a variant of uncertain significance for Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome, autosomal dominant The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); de novo variant (PS2 downgraded to moderate); Well-established functional studies show a deleterious effect (PS3 downgraded to supporting). |
| Illumina Laboratory Services, |
RCV001093624 | SCV002038545 | likely pathogenic | Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome | 2021-06-08 | criteria provided, single submitter | clinical testing | The EIF2AK2 c.1382C>G (p.Ser461Cys) variant is a missense variant that is located in the protein-kinase domain of the EIF2AK2 protein (Mao et al. 2020). The p.Ser461Cys variant has been reported in a de novo state in one individual with leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome (Mao et al. 2020). The p.Ser461Cys variant is not found in version 2.1.1 or version 3.1.1 of the Genome Aggregation Database in a region of good sequence coverage, which suggests the variant is rare. Functional studies in patient fibroblasts for the p.Ser461Cys variant demonstrated impaired kinase activity with consistent reduction in p-EIF2S1 levels and decrease in ATF4 levels, a downstream target of p-EIF2S1 (Mao et al. 2020). Based on the collective evidence and identification of this variant in a de novo state, the p.Ser461Cys variant is classified as likely pathogenic for leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome. |
| OMIM | RCV001093624 | SCV001250816 | pathogenic | Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome | 2022-02-10 | no assertion criteria provided | literature only |