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

gnomAD frequency: 0.00029  dbSNP: rs80338671

Total submissions: 15

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	2022-06-27	criteria provided, single submitter	clinical testing	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, 23034915, 30293248, 34426522, 34297361)
Genetic Services Laboratory, University of Chicago	RCV001172459	SCV000594937	uncertain significance	not specified	2019-06-19	criteria provided, single submitter	clinical testing
Invitae	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	RCV001172459	SCV001338529	uncertain significance	not specified	2023-01-03	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 homozygote. This frequency is not significantly higher than expected 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), although the phase of these two variants was not specified (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. Ten submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments: Seven classified it as VUS while three classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly 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