rs80338671
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PP3_ModeratePP5BS1_SupportingBS2
The NM_000158.4(GBE1):c.986A>G(p.Tyr329Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000553 in 1,597,402 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000158.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| GBE1 | ENST00000429644.7 | c.986A>G | p.Tyr329Cys | missense_variant | Exon 7 of 16 | 1 | NM_000158.4 | ENSP00000410833.2 | ||
| GBE1 | ENST00000489715.1 | c.863A>G | p.Tyr288Cys | missense_variant | Exon 7 of 16 | 2 | ENSP00000419638.1 | |||
| GBE1 | ENST00000498468.1 | n.536A>G | non_coding_transcript_exon_variant | Exon 4 of 4 | 3 |
Frequencies
GnomAD3 genomes 0.000526 AC: 80AN: 151990Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000455 AC: 113AN: 248464Hom.: 1 AF XY: 0.000571 AC XY: 77AN XY: 134792
GnomAD4 exome AF: 0.000556 AC: 804AN: 1445292Hom.: 5 Cov.: 27 AF XY: 0.000614 AC XY: 442AN XY: 720126
GnomAD4 genome 0.000519 AC: 79AN: 152110Hom.: 0 Cov.: 32 AF XY: 0.000417 AC XY: 31AN XY: 74366
ClinVar
Submissions by phenotype
Glycogen storage disease, type IV Pathogenic:3Uncertain:6
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
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The p.Tyr329Cys variant in GBE1 has been reported in 6 individuals with GBE1-related disorders (PMID: 30293248, 23034915) and has been identified in 0.09% (27/30586) of South Asian chromosomes by the Genome Aggregation Database, including one homozygote (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs80338671). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#: 371439) and has been interpreted as likely pathogenic by Counsyl, Invitae, and Women's Health and Genetics (Laboratory Corporation of America, LabCorp), and as uncertain significance by GeneDx, Illumina Clinical Services Laboratory (Illumina), Genetic Services Laboratory (University of Chicago), Nilou-Genome Lab, and Al Jalila Children's Genomics Center (Al Jalila Childrens Speciality Hospital). Of the 6 affected individuals, 1 of those were homozygote, which increases the likelihood that the p.Tyr329Cys variant is pathogenic (PMID: 30293248). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Tyr329Ser, has been reported in association with disease in (the literature and ClinVar), supporting that a change at this position may not be tolerated (PMID: 8613547, 9851430, 20655781, 23034915, 25133958, 25665141, 33332610, 26385640/Variation ID: 2777). In summary, the clinical significance of the p.Tyr329Cys variant is uncertain. ACMG/AMP Criteria applied: PP3, PM3_supporting, PM5 (Richards 2015). -
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Variant summary: GBE1 c.986A>G (p.Tyr329Cys) results in a non-conservative amino acid change located in the Glycosyl hydrolase, family 13, catalytic domain (IPR006047) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00045 in 248464 control chromosomes, predominantly at a frequency of 0.00088 within the South Asian subpopulation in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in GBE1 causing Glycogen Storage Disease, Type IV (0.00045 vs 0.0013), allowing no conclusion about variant significance. c.986A>G has been reported in the literature in five individuals affected with Adult Polyglucosan Body Disease who also carried a second variant (N556Y) (Mochel_2012). The variant has also been reported in at least two individuals with glycogen storage disease, one homozygote and one heterozygote without a reported second mutation (Nair_2018, Isik_2019). In addition, another missense variant at the same codon (Y329S) has been classified as pathogenic and is a common mutation within affected Ashkenazi Jewish patients (Mochel_2012), suggesting the tyrosine residue at position 329 is critical for GBE1 protein function. These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 31207142, 31980526, 31209396, 31319225, 34426522, 27528516, 23034915, 30293248, 28716262). ClinVar contains an entry for this variant (Variation ID: 371439). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
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The missense c.986A>G p.Tyr329Cys variant in the GBE1 gene has been reported in 6 individuals with GBE1-related disorders Nair, Pratibha et al., 2018. This variant is reported with the allele frequency 0.04% in the gnomAD Exomes and novel in 1000 Genomes. It is submitted to ClinVar as Likely Pathogenic/ Uncertain Significance multiple submissions. The amino acid Tyrosine at position 329 is changed to a Cysteine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Tyr329Cys in GBE1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -
not provided Pathogenic:3Uncertain:2
Observed in apparent homozygous state in an infant with persistent fever, cough, shortening of proximal extremities, and dysmorphic features (PMID: 38592052); Observed in apparent homozygous state in an adult with progressive weakness in extremities, dyspnea, dysphagia, and abnormal EMG (PMID: 38127101); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31980526, 31207142, 31319225, 31209396, 8613547, 30293248, 34426522, 34297361, 36703223, 37510298, 38592052, 38127101, 23034915, 9851430, 25665141, 27528516) -
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The GBE1 c.986A>G; p.Tyr329Cys variant (rs80338671) is reported in the literature as both homozygotes and heterozygotes in several individuals affected with adult polyglucosan body disease (APBD) (Krenn 2024, Latif 2024, Mochel 2012, Nair 2018). In heterozygous individuals, either a second variant was not detected or else was not known to be pathogenic (Mochel 2012). The p.Tyr329Cys variant is found in the South Asian population with an allele frequency of 0.09% (27/30586 alleles, including one homozygote) in the Genome Aggregation Database (v2.1.1). The tyrosine at codon 329 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.97). Additionally, another variant at this codon (c.986A>C, p.Tyr329Ser) is a founder pathogenic variant detected in homozygous state in individuals of Ashkenazi-Jewish descent affected with APBD (Lossos 1998, Mochel 2012). Based on available information, this variant is considered to be likely pathogenic. References: Krenn M et al. Next-generation sequencing and comprehensive data reassessment in 263 adult patients with neuromuscular disorders: insights into the gray zone of molecular diagnoses. J Neurol. 2024 Apr. PMID: 38127101 Latif M et al. Identification of Novel and Recurrent Variants in BTD, GBE1, AGL and ASL Genes in Families with Metabolic Disorders in Saudi Arabia. J Clin Med. 2024 Feb 20. PMID: 38592052 Lossos et al. Adult polyglucosan body disease in Ashkenazi Jewish patients carrying the Tyr329Ser mutation in the glycogen-branching enzyme gene. Ann Neurol. 1998 Dec;44(6):867-72. PMID: 9851430. Mochel et al. Adult polyglucosan body disease: Natural History and Key Magnetic Resonance Imaging Findings. Ann Neurol. 2012 Sep;72(3):433-41. PMID: 23034915. Nair et al. Contribution of next generation sequencing in pediatric practice in Lebanon. A Study on 213 cases. Mol Genet Genomic Med. 2018 Nov;6(6):1041-1052. PMID: 30293248. -
BS2, PP3, PP4, PM1, PM3, PM5 -
GBE1: PM2:Supporting -
not specified Uncertain:2
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Adult polyglucosan body disease Uncertain:2
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
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Glycogen storage disease, type IV;C1849722:Adult polyglucosan body disease Pathogenic:1
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Glycogen storage disease, type IV;C1856301:Glycogen storage disease IV, classic hepatic Pathogenic:1
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 329 of the GBE1 protein (p.Tyr329Cys). This variant is present in population databases (rs80338671, gnomAD 0.08%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individuals with adult polyglucosan body disease (PMID: 23034915). ClinVar contains an entry for this variant (Variation ID: 371439). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GBE1 protein function with a positive predictive value of 95%. This variant disrupts the p.Tyr329 amino acid residue in GBE1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8613547, 25665141, 26199317, 26385640). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
GBE1-related disorder Uncertain:1
The GBE1 c.986A>G variant is predicted to result in the amino acid substitution p.Tyr329Cys. This variant has been reported in the compound heterozygous state in five patients affected with adult polyglucosan body disease (APBD), four of which were of Ashkenazi Jewish ancestry (Mochel et al. 2012. PubMed ID: 23034915). The results of functional assays and genetic segregation data were not clearly presented in this study; in the absence of such conclusive results the authors concluded that the c.986A>G variant was likely pathogenic. Of note, a change involving the same amino acid (p.Tyr329Ser) has been reported to be causative for glycogen storage disease type IV as well as for APBD (Bao et al. 1996. PubMed ID: 8613547; Lossos et al. 1998. PubMed ID: 9851430). The c.986A>G (p.Tyr329Cys) variant is present at a minor allele frequency of up to ~0.088% in gnomAD, with 1 homozygote listed. Taken together, although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at