chr3-184140584-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_003907.3(EIF2B5):c.1010A>G(p.His337Arg) variant causes a missense 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_003907.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
EIF2B5 | NM_003907.3 | c.1010A>G | p.His337Arg | missense_variant | Exon 7 of 16 | ENST00000648915.2 | NP_003898.2 | |
EIF2B5 | XM_047449148.1 | c.1010A>G | p.His337Arg | missense_variant | Exon 7 of 11 | XP_047305104.1 | ||
EIF2B5 | XM_011513265.1 | c.260A>G | p.His87Arg | missense_variant | Exon 3 of 12 | XP_011511567.1 | ||
EIF2B5 | XM_011513266.4 | c.173A>G | p.His58Arg | missense_variant | Exon 2 of 11 | XP_011511568.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Vanishing white matter disease Pathogenic:1
The variant identified not been previously reported in public databases. This variant was identified in a patient diagnosed with Vanishing white matter leukodystrophy, a disease characterized by variable neurologic features, including progressive cerebellar ataxia, spasticity, and cognitive impairment associated with white matter lesions on brain imaging. We consider that these variants in compound heterozygosis are probably pathogenic because they are in a critical region and coding for the EIF2B5 gene; The gene has previously been associated with this disease as reported in the OMIM database and PubMed (Sharma et al., 2015; Woody et al., 2015). -
not specified Uncertain:1
Variant summary: EIF2B5 c.1010A>G (p.His337Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251454 control chromosomes. c.1010A>G has been reported in the literature in compound heterozygous individuals affected with Leukoencephalopathy With Vanishing White Matter, including two affected individuals in one family (Rodrguez-Quiroga_2015, Cohen_2020, Benzoni_2023). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 37171481, 31418856, 25989649). ClinVar contains an entry for this variant (Variation ID: 590971). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at