Submissions for variant NM_001958.5(EEF1A2):c.796C>T (p.Arg266Trp)

dbSNP: rs1555883505

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523934	SCV000617130	pathogenic	not provided	2022-08-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect on protein synthesis and cellular stress response resulting in cell toxicity (Carvill et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30370994, 26795593, 19909265, 32196822, 32429945, 32062104, 31785789)
Ambry Genetics	RCV000623103	SCV000740903	pathogenic	Inborn genetic diseases	2015-06-01	criteria provided, single submitter	clinical testing
Undiagnosed Diseases Network, NIH	RCV000626030	SCV000746643	pathogenic	Developmental and epileptic encephalopathy, 33	2017-04-19	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763059	SCV000893544	likely pathogenic	Intellectual disability, autosomal dominant 38; Developmental and epileptic encephalopathy, 33	2018-10-31	criteria provided, single submitter	clinical testing
Epilepsy Neurogenetics Initiative, Children's Hospital of Philadelphia	RCV001030066	SCV001192846	pathogenic	EEF1A2-related developmental and degenerative epileptic-dyskinetic encephalopathy	2020-02-13	criteria provided, single submitter	research	The EEF1A2 c.796C>T; p.Arg266Trp variant has been identified in three individuals with a developmental and epileptic encephalopathy characterized by global developmental delays, moderate to profound intellectual disability, and infantile or early childhood onset epilepsy in two individuals. Two individuals had a hyperkinetic movement disorder characterized by choreoathetosis. The variant is confirmed de novo in all three individuals. The 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 pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004527627	SCV001482051	pathogenic	EEF1A2-related disorder	2021-01-26	criteria provided, single submitter	clinical testing	Variant summary: EEF1A2 c.796C>T (p.Arg266Trp) results in a non-conservative amino acid change located in the domain 2 (IPR004161) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 241660 control chromosomes (gnomAD). c.796C>T has been reported in the literature in individuals affected with EEF1A2-Related Disorders, with varying phenotypes including developmental delay, intellectual disability, seizures and movement disorders. The first report of the variant was in a patient with infantile onset of focal epilepsy and temporal lobe epilepsy (Helbig_2016). A second report, which may have patient overlap with the patient described in Helbig_2016, reports the variant in three patients with developmental delay and intellectual disability, two of them also had seizures (Carvill_2020). Additional reports of the variant are in a patient with developmental delay, frontal lobe intractable epilepsy, neurogenic bladder, and choreoathetoid cerebral palsy (Fernandez_2017, ASHG poster abstract) and in a patient with dysphagia, muscular hypertonia, mental retardation and brain dysplasia (Wang_2020). All cases have been reported as de novo mutations. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (4x) / likely pathogenic (1x) or VUS (1x). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV001336410	SCV001529788	pathogenic	Intellectual disability, autosomal dominant 38	2018-02-27	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Revvity Omics, Revvity	RCV000523934	SCV002022164	pathogenic	not provided	2021-01-20	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000523934	SCV002064063	pathogenic	not provided	2021-11-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000626030	SCV001215914	uncertain significance	Developmental and epileptic encephalopathy, 33	2020-01-13	flagged submission	clinical testing	This sequence change replaces arginine with tryptophan at codon 266 of the EEF1A2 protein (p.Arg266Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with EEF1A2-related disease (PMID: 26795593). ClinVar contains an entry for this variant (Variation ID: 449242). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.