rs113994064
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_Very_Strong
The NM_003907.3(EIF2B5):c.944G>A(p.Arg315His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,613,964 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R315C) has been classified as Pathogenic.
Frequency
Consequence
NM_003907.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EIF2B5 | NM_003907.3 | c.944G>A | p.Arg315His | missense_variant | 7/16 | ENST00000648915.2 | |
EIF2B5 | XM_047449148.1 | c.944G>A | p.Arg315His | missense_variant | 7/11 | ||
EIF2B5 | XM_011513265.1 | c.194G>A | p.Arg65His | missense_variant | 3/12 | ||
EIF2B5 | XM_011513266.4 | c.107G>A | p.Arg36His | missense_variant | 2/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EIF2B5 | ENST00000648915.2 | c.944G>A | p.Arg315His | missense_variant | 7/16 | NM_003907.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152072Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251418Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135880
GnomAD4 exome AF: 0.0000219 AC: 32AN: 1461892Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18AN XY: 727246
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152072Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74292
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 13, 2022 | 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) - |
Vanishing white matter disease Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 11, 2022 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Leukoencephalopathy with vanishing white matter 5 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 24, 2007 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at