Submissions for variant NM_001958.5(EEF1A2):c.1295C>T (p.Thr432Met)

dbSNP: rs2082362479

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Epilepsy Neurogenetics Initiative, Children's Hospital of Philadelphia	RCV001030068	SCV001192848	likely pathogenic	EEF1A2-related developmental and degenerative epileptic-dyskinetic encephalopathy	2020-02-13	criteria provided, single submitter	research	The EEF1A2 c.1295C>T; p.Thr432Met variant has been identified in an individual with a developmental and epileptic encephaloathy characterized by myoclonic seizures beginning at 35 months and generalized dystonia. This individual had global developmental delays with moderate to severe intellectual disability. The variant was inherited from an unaffected parent who is somatic mosaic. This variant is absent from population databases (ExAC, gnomAD), and is predicted to have a damaging effect on the protein by in silico models. Therefore, this variant has been classified as likely pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002272389	SCV002557279	pathogenic	Intellectual disability, autosomal dominant 38	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, gain-of-function has been suggested (PMID: 32160274). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to methionine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported in a patient with intellectual disability (MIM#616393) and one with EEF1A2-related neurodevelopmental disorder (MIM#616409); one of whom was a de novo event and the other maternally mosaic (DECIPHER, PMID: 32196822). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV002463773	SCV002758031	likely pathogenic	Intellectual disability, autosomal dominant 38; Developmental and epileptic encephalopathy, 33	2022-12-05	criteria provided, single submitter	clinical testing
Invitae	RCV003768929	SCV004640904	likely pathogenic	Developmental and epileptic encephalopathy, 33	2023-07-13	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 432 of the EEF1A2 protein (p.Thr432Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with developmental and epileptic encephalopathy (PMID: 32196822). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 830077). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on EEF1A2 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Department of Genetics, Robert DEBRE University Hospital	RCV003444743	SCV004171545	pathogenic	not provided	2019-02-15	no assertion criteria provided	clinical testing