Submissions for variant NM_000158.4(GBE1):c.986A>G (p.Tyr329Cys)

gnomAD frequency: 0.00029  dbSNP: rs80338671

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000410814	SCV000487021	likely pathogenic	Glycogen storage disease, type IV	2016-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000490240	SCV000577621	uncertain significance	not provided	2024-08-21	criteria provided, single submitter	clinical testing	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)
Genetic Services Laboratory, University of Chicago	RCV001172459	SCV000594937	uncertain significance	not specified	2019-06-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000529291	SCV000626777	likely pathogenic	Glycogen storage disease, type IV; Glycogen storage disease IV, classic hepatic	2024-01-29	criteria provided, single submitter	clinical testing	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). 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 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.
Illumina Laboratory Services, Illumina	RCV000410814	SCV001305737	uncertain significance	Glycogen storage disease, type IV	2017-04-27	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV001145097	SCV001305738	uncertain significance	Adult polyglucosan body disease	2017-04-27	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000410814	SCV001338529	likely pathogenic	Glycogen storage disease, type IV	2024-03-15	criteria provided, single submitter	clinical testing	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.
Genome-Nilou Lab	RCV000410814	SCV001810439	uncertain significance	Glycogen storage disease, type IV	2021-07-22	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001145097	SCV001810441	uncertain significance	Adult polyglucosan body disease	2021-07-22	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001172459	SCV001984267	uncertain significance	not specified	2020-07-23	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000410814	SCV002097105	uncertain significance	Glycogen storage disease, type IV	2022-01-27	criteria provided, single submitter	curation	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).
Genetics and Molecular Pathology, SA Pathology	RCV000410814	SCV002557032	likely pathogenic	Glycogen storage disease, type IV	2021-05-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000490240	SCV002563778	uncertain significance	not provided	2022-11-01	criteria provided, single submitter	clinical testing	GBE1: PM2:Supporting
Revvity Omics, Revvity	RCV000490240	SCV003832932	likely pathogenic	not provided	2022-09-30	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000410814	SCV004198699	uncertain significance	Glycogen storage disease, type IV	2023-07-15	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000410814	SCV004806797	uncertain significance	Glycogen storage disease, type IV	2024-03-26	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000410814	SCV005042802	uncertain significance	Glycogen storage disease, type IV		criteria provided, single submitter	clinical testing	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000490240	SCV005413590	likely pathogenic	not provided	2024-04-12	criteria provided, single submitter	clinical testing	BS2, PP3, PP4, PM1, PM3, PM5
PreventionGenetics, part of Exact Sciences	RCV004732865	SCV005345200	uncertain significance	GBE1-related disorder	2024-04-09	no assertion criteria provided	clinical testing	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.