VCV000830077.7 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(5)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 830077 Accession: VCV000830077.7

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 20q13.33 20: 63488395 (GRCh38) [ NCBI UCSC ] 20: 62119748 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 6, 2020	Jul 23, 2024	Jul 13, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001958.5:c.1295C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001949.1:p.Thr432Met	missense
NC_000020.11:g.63488395G>A
NC_000020.10:g.62119748G>A
NG_034083.1:g.15921C>T

Protein change

T432M

Other names

Canonical SPDI

NC_000020.11:63488394:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

dbSNP: rs2082362479 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
EEF1A2		No evidence available	No evidence available	GRCh38 GRCh37	506	667

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
EEF1A2-related developmental and degenerative epileptic-dyskinetic encephalopathy	Likely pathogenic (1)	criteria provided, single submitter	Feb 13, 2020	RCV001030068.1
Developmental and epileptic encephalopathy, 33 Intellectual disability, autosomal dominant 38	Likely pathogenic (1)	criteria provided, single submitter	Dec 5, 2022	RCV002463773.2
Intellectual disability, autosomal dominant 38	Pathogenic (1)	criteria provided, single submitter	Feb 2, 2022	RCV002272389.3
Developmental and epileptic encephalopathy, 33	Likely pathogenic (1)	criteria provided, single submitter	Jul 13, 2023	RCV003768929.2
not provided	Pathogenic (1)	no assertion criteria provided	Feb 15, 2019	RCV003444743.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Feb 13, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	EEF1A2-related developmental and degenerative epileptic-dyskinetic encephalopathy (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Epilepsy Neurogenetics Initiative, Children's Hospital of Philadelphia Accession: SCV001192848.1 First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020	Comment: 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 … (more) 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. (less) Clinical Features: Global developmental delay (present) , Intellectual disability, severe (present) , Generalized myoclonic seizures (present) , Generalized dystonia (present) , Cerebral cortical atrophy (present) , Muscular … (more) Global developmental delay (present) , Intellectual disability, severe (present) , Generalized myoclonic seizures (present) , Generalized dystonia (present) , Cerebral cortical atrophy (present) , Muscular hypotonia (present) (less)
Likely pathogenic (Dec 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, autosomal dominant 38 Developmental and epileptic encephalopathy, 33 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV002758031.1 First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022	Clinical Features: Delayed speech and language development (present) , Motor delay (present) , Absent speech (present) , Talipes (present) , EEG abnormality (present) , Limb hypertonia (present) … (more) Delayed speech and language development (present) , Motor delay (present) , Absent speech (present) , Talipes (present) , EEG abnormality (present) , Limb hypertonia (present) , Mildly elevated creatine kinase (present) , Axial hypotonia (present) , Monocular strabismus (present) (less)
Likely pathogenic (Jul 13, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Developmental and epileptic encephalopathy, 33 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004640904.1 First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024	Publications: PubMed (1) PubMed: 32196822 Comment: 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). … (more) 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. (less)
Pathogenic (Feb 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, autosomal dominant 38 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002557279.2 First in ClinVar: Aug 08, 2022 Last updated: Jul 23, 2024	Publications: PubMed (2) PubMed: 32160274‚ 32196822 Comment: 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 … (more) 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 (less)
Pathogenic (Feb 15, 2019)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: de novo	Department of Genetics, Robert DEBRE University Hospital Accession: SCV004171545.1 First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023	Clinical Features: Intellectual disability (present)

Comment:

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.

Comment:

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.

Comment:

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

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Damaging de novo missense variants in EEF1A2 lead to a developmental and degenerative epileptic-dyskinetic encephalopathy.	Carvill GL	Human mutation	2020	PMID: 32196822
Recapitulation of the EEF1A2 D252H neurodevelopmental disorder-causing missense mutation in mice reveals a toxic gain of function.	Davies FCJ	Human molecular genetics	2020	PMID: 32160274

Text-mined citations for rs2082362479 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2082362479 ...