NM_020365.5(EIF2B3):c.272G>A (p.Arg91His) AND Vanishing white matter disease

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jun 11, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000763340.4

Allele description [Variation Report for NM_020365.5(EIF2B3):c.272G>A (p.Arg91His)]

NM_020365.5(EIF2B3):c.272G>A (p.Arg91His)

Gene:

EIF2B3:eukaryotic translation initiation factor 2B subunit gamma [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p34.1

Genomic location:

Preferred name:

NM_020365.5(EIF2B3):c.272G>A (p.Arg91His)

HGVS:

NC_000001.11:g.44978337C>T
NG_015864.1:g.13353G>A
NM_001166588.3:c.272G>A
NM_001261418.2:c.272G>A
NM_020365.5:c.272G>AMANE SELECT
NP_001160060.1:p.Arg91His
NP_001248347.1:p.Arg91His
NP_065098.1:p.Arg91His
NC_000001.10:g.45444009C>T
NM_020365.4:c.272G>A

Protein change:

R91H

Links:

dbSNP: rs141988913

NCBI 1000 Genomes Browser:

rs141988913

Molecular consequence:

NM_001166588.3:c.272G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001261418.2:c.272G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_020365.5:c.272G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Vanishing white matter disease
Synonyms:: CACH syndrome; Childhood ataxia with diffuse central nervous system hypomyelination; Leukoencephalopathy with vanishing white matter; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0800448; MedGen: C1858991; Orphanet: 99853; OMIM: PS603896

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000894022	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 31, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005204480	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Jun 11, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 33432707, 34745209, 22312164, 25079571 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000894022

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Oct 31, 2018)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV005204480

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Jun 11, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Vanishing white matter: Eukaryotic initiation factor 2B model and the impact of missense mutations.

Slynko I, Nguyen S, Hamilton EMC, Wisse LE, de Esch IJP, de Graaf C, Bruning JB, Proud CG, Abbink TEM, van der Knaap MS.

Mol Genet Genomic Med. 2021 Mar;9(3):e1593. doi: 10.1002/mgg3.1593. Epub 2021 Jan 12.

PubMed [citation]

PMID:: 33432707
PMCID:: PMC8104162

See all PubMed Citations (5)

PMC

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From Fulgent Genetics, Fulgent Genetics, SCV000894022.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005204480.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: EIF2B3 c.272G>A (p.Arg91His) results in a non-conservative amino acid change located in the Nucleotidyl transferase domain (IPR005835) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251392 control chromosomes. c.272G>A has been reported in the literature in individuals affected with Leukoencephalopathy With Vanishing White Matter (examples: Robinson_2014, LaPiana_2014, Slynko_2021, Deng_2021). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 34745209, 22312164, 25079571, 33432707). ClinVar contains an entry for this variant (Variation ID: 431961). Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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