rs1141814
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_000157.4(GBA1):c.259C>T(p.Arg87Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,614,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R87Q) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000157.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GBA1 | NM_000157.4 | c.259C>T | p.Arg87Trp | missense_variant | 3/11 | ENST00000368373.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GBA1 | ENST00000368373.8 | c.259C>T | p.Arg87Trp | missense_variant | 3/11 | 1 | NM_000157.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152130Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251272Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135824
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461872Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6AN XY: 727236
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152248Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74444
ClinVar
Submissions by phenotype
Gaucher disease Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 10, 2016 | Variant summary: The GBA c.259C>T (p.Arg87Trp) variant, located in the Glycosyl hydrolase domain, causes a missense change involving a conserved nucleotide with 5/5 in silico tools predict a damaging outcome, which a functional study, Grace_1997, supports these predictions. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency 2/121120 (1/60560), which does not exceed the estimated maximal expected allele frequency for a pathogenic GBA variant of 1/200 (0.005). This variant has been reported in numerous GD patients, who were homozygous and compound heterozygous for the variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 16, 2017 | - - |
Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 22, 2020 | The p.Arg87Trp variant in GBA has been reported in at least 12 individuals with Gaucher disease, segregated with disease in 4 affected relatives from 2 families (PMID: 28506293, 28727984, 28947706, 7655857, 17574891, 9153297, 9295080, 17059888), and has been identified in 0.012% (2/16234) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1141814). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 4321) as pathogenic by OMIM and Integrated Genetics. In vitro functional studies provide some evidence that the p.Arg87Trp variant may slightly impact protein function (PMID: 9153297). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in one affected homozygote and in combination with reported pathogenic variants in 7 individuals with Gaucher disease increases the likelihood that the p.Arg87Trp variant is pathogenic (VariationID: 4288, 4328, 65570; PMID: 28506293, 28727984, 28947706, 7655857, 17574891, 9295080). The phenotype of individuals compound heterozygous for this variant is highly specific for Gaucher disease based on significantly reduced beta-glucosidase activity in the leukocytes consistent with disease (PMID: 28506293, 9295080). In summary, this variant meets criteria to be classified as pathogenic for Gaucher disease in an autosomal recessive manner based on the presence of the variant in combination with other pathogenic variants in affected individuals, patient's phenotypes being highly specific for the gene, cosegregation with disease, and functional studies. ACMG/AMP Criteria applied: PM3_very-strong, PM2_supporting, PP3, PP4, PS3_supporting, PP1 (Richards 2015). - |
Gaucher disease type I Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 03, 1997 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | Jan 25, 2024 | A compound heterozygous missense variation in exon 3 of the GBA gene that results in the amino acid substitution of Trptophan for Arginine at codon 87 was detected. The observed variant c.259C>T (p.Arg87Trp) has a minor allele frequency of 0.0028% in the gnomAD databases. The in silico prediction of the variant is disease causing by DANN and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Feb 13, 2020 | PS3, PS4_moderate, PM2, PP1, PP4 - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 23, 2019 | - - |
Gaucher disease type II;C0268251:Gaucher disease type III;C0752347:Lewy body dementia;C1842704:Gaucher disease perinatal lethal;C1856476:Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome;C1961835:Gaucher disease type I;C3160718:Parkinson disease, late-onset Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 17, 2021 | - - |
See cases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Apr 02, 2020 | ACMG classification criteria: PS3, PS4, PM2, PM3, PP2 - |
Lewy body dementia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at