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NM_003907.3(EIF2B5):c.944G>A (p.Arg315His) AND not provided

Germline classification:
Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:
Jan 31, 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:
RCV001070077.7

Allele description [Variation Report for NM_003907.3(EIF2B5):c.944G>A (p.Arg315His)]

NM_003907.3(EIF2B5):c.944G>A (p.Arg315His)

Gene:
EIF2B5:eukaryotic translation initiation factor 2B subunit epsilon [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
3q27.1
Genomic location:
Preferred name:
NM_003907.3(EIF2B5):c.944G>A (p.Arg315His)
HGVS:
  • NC_000003.12:g.184140518G>A
  • NG_015826.1:g.10497G>A
  • NM_003907.3:c.944G>AMANE SELECT
  • NP_003898.2:p.Arg315His
  • LRG_1278t1:c.944G>A
  • LRG_1278:g.10497G>A
  • LRG_1278p1:p.Arg315His
  • NC_000003.11:g.183858306G>A
  • NM_003907.2:c.944G>A
  • Q13144:p.Arg315His
Protein change:
R315H; ARG315HIS
Links:
UniProtKB: Q13144#VAR_012327; OMIM: 603945.0009; dbSNP: rs113994064
NCBI 1000 Genomes Browser:
rs113994064
Molecular consequence:
  • NM_003907.3:c.944G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001235287Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Jan 31, 2024)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV002765624GeneDx
criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)
Likely pathogenic
(Dec 13, 2022)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Progressive megalencephaly due to specific EIF2Bepsilon mutations in two unrelated families.

Passemard S, Gelot A, Fogli A, N'Guyen S, Barnerias C, Niel F, Doummar D, Arbues AS, Mignot C, de Villemeur TB, Ponsot G, Boespflug-Tanguy O, Rodriguez D.

Neurology. 2007 Jul 24;69(4):400-2. No abstract available.

PubMed [citation]
PMID:
17646634

Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter.

Leegwater PA, Vermeulen G, Könst AA, Naidu S, Mulders J, Visser A, Kersbergen P, Mobach D, Fonds D, van Berkel CG, Lemmers RJ, Frants RR, Oudejans CB, Schutgens RB, Pronk JC, van der Knaap MS.

Nat Genet. 2001 Dec;29(4):383-8.

PubMed [citation]
PMID:
11704758
See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001235287.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 315 of the EIF2B5 protein (p.Arg315His). This variant is present in population databases (rs113994064, gnomAD 0.007%). This missense change has been observed in individuals with leukoencephalopathy with vanishing white matter (PMID: 11704758, 17646634; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5950). 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) performed at Invitae indicates that this missense variant is not expected to disrupt EIF2B5 protein function with a negative predictive value of 80%. This variant disrupts the p.Arg315 amino acid residue in EIF2B5. Other variant(s) that disrupt this residue have been observed in individuals with EIF2B5-related conditions (PMID: 11704758, 15136673, 21307862), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From GeneDx, SCV002765624.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Functional studies in lymphocytes from a patient who had the R315H variant as well as another EIF2B5 variant suggest reduction of guanine exchange activity compared to wild-type; however, additional studies are needed to validate the functional effect of this variant on its own (Horzinski et al., 2010); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21307862, 17646634, 26162493, 20016818, 15136673, 11704758, 33084218, 34745209, 20958979)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024