rs113994014

Positions:

• chr14-75005874-AATGGCT-ATG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_014239.4(EIF2B2):​c.607_612delinsTG​(p.Met203TrpfsTer2) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EIF2B2 NM_014239.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 9.62

Genes affected

EIF2B2 (HGNC:3258): (eukaryotic translation initiation factor 2B subunit beta) This gene encodes the beta subunit of eukaryotic initiation factor-2B (EIF2B). EIF2B is involved in protein synthesis and exchanges GDP and GTP for its activation and deactivation. [provided by RefSeq, Aug 2011]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-75005875-ATGGCT-TG is Pathogenic according to our data. Variant chr14-75005875-ATGGCT-TG is described in ClinVar as [Pathogenic]. Clinvar id is 4340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF2B2	NM_014239.4	c.607_612delinsTG	p.Met203TrpfsTer2	frameshift_variant	5/8	ENST00000266126.10	NP_055054.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF2B2	ENST00000266126.10	c.607_612delinsTG	p.Met203TrpfsTer2	frameshift_variant	5/8	1	NM_014239.4	ENSP00000266126	P1
	ENST00000554430.1	n.287-959_287-954delinsCA		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Vanishing white matter disease Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 20, 2023	Variant summary: EIF2B2 c.607_612delinsTG (p.Met203TrpfsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251476 control chromosomes (gnomAD). c.607_612delinsTG has been reported in the literature in individuals affected with Leukoencephalopathy With Vanishing White Matter (e.g., Slynko_2020). These data indicate that the variant is very likely to be associated with disease. The following publication was ascertained in the context of this evaluation (PMID: 33432707). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 18, 2018	The EIF2B2 c.607_612delATGGCTinsTG (p.Met203TrpfsTer2) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Met203TrpfsTer2 variant has been reported in at least three studies in which it is found in a compound heterozygous state with a missense variant in at least three patients with childhood ataxia with central nervous system hypomyelination/vanishing white matter (Leegwater et al. 2001; Fogli et al. 2003; Ohlenbusch et al. 2005). The p.Met203TrpfsTer2 variant was absent from 700 control chromosomes and is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium, or the Genome Aggregation Database. Li et al. (2004) performed functional studies in HEK293 cells, in which the p.Met203TrpfsTer2 variant protein was expressed with wild type versions of the other proteins involved in the EIF2B heteropentamer complex. SDS-PAGE and Western blotting for myc-tagged proteins showed that the p.Met203TrpfsTer2 variant was not able to form complexes with the other proteins suggesting that the C-terminal is needed for interaction and normal function. Based on the evidence and the potential impact of frameshift variants, the p.Met203TrpfsTer2 variant is considered pathogenic for childhood ataxia with central nervous system hypomyelination/vanishing white matter. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as pathogenic and reported on 03/14/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2020	Reported previously in association with vanishing white matter (VWM) disease in a patient who had a second variant in EIF2B2 (Leegwater et al., 2001); Previously reported in an adult female with ovarian failure and brain MRI anomalies similar to those seen in patients with VWM; this individual also had a second variant in EIF2B2 (Fogli et al., 2003); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 11704758, 12707859, 31438897) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change creates a premature translational stop signal (p.Met203Trpfs*2) in the EIF2B2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EIF2B2 are known to be pathogenic (PMID: 11704758, 12707859). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This premature translational stop signal has been observed in individual(s) with leukoencephalopathy with vanishing white matter (PMID: 11704758). For these reasons, this variant has been classified as Pathogenic. -

Leukoencephalopathy with vanishing white matter 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2003

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs113994014; hg19: chr14-75472578;