Submissions for variant NM_000158.4(GBE1):c.986A>C (p.Tyr329Ser)

dbSNP: rs80338671

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000304728	SCV000446301	pathogenic	GBE1-related disorder	2018-09-07	criteria provided, single submitter	clinical testing	The GBE1 c.986A>C (p.Tyr329Ser) missense variant has been reported in at least six studies in which it is found in a total of 82 individuals with glycogen storage disease type IV or adult polyglucosan body disease, including in 48 in a homozygous state, in 25 in a compound heterozygous state, and in nine in a heterozygous state where a second variant was not detected (Bao et al. 1996; Lossos et al. 1998; Roe et al. 2010; DiMauro and Spiegel 2011; Mochel et al. 2013; Akman et al. 2015). The p.Tyr329Ser variant was absent from 143 controls but is reported at a frequency of 0.00045 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies demonstrated that the expression of recombinant protein carrying the p.Tyr329Ser variant resulted in a drastically reduced protein yield and solubility, suggesting that the variant leads to protein misfolding (Froese et al. 2015). The variant has also been shown to result in decreased enzyme activity ranging from undetectable levels to 50% of wild type (Bao et al. 1996; Lossos et al. 1998; Mochel et al. 2013; Akman et al. 2015). Based on the collective evidence, the p.Tyr329Ser variant is classified as pathogenic for GBE1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx	RCV000493505	SCV000582785	pathogenic	not provided	2022-06-03	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that the variant is associated with 50% of GBE activity when compared to wild type (Bao et al., 1996); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Common pathogenic variant in the Ashkenazi Jewish population (Akman et al., 2015); This variant is associated with the following publications: (PMID: 24082139, 30185673, 20655781, 26385640, 30228975, 25133958, 31692161, 34103343, 31980526, 31589614, 9851430, 32746448, 33332610, 25665141, 8613547)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000555363	SCV000626776	pathogenic	Glycogen storage disease, type IV; Glycogen storage disease IV, classic hepatic	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 329 of the GBE1 protein (p.Tyr329Ser). This variant is present in population databases (rs80338671, gnomAD 0.6%). This missense change has been observed in individual(s) with adult polyglucosan body disease (PMID: 8613547, 20655781, 24082139, 25133958, 25665141). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 8613547, 20655781, 24082139, 25133958, 25665141). ClinVar contains an entry for this variant (Variation ID: 2777). 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%. Experimental studies have shown that this missense change affects GBE1 function (PMID: 8613547, 26199317, 26385640). For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000493505	SCV000700628	pathogenic	not provided	2017-01-27	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000493505	SCV000801198	pathogenic	not provided	2019-09-03	criteria provided, single submitter	clinical testing	PS3, PS4_moderate, PM2, PM3, PP1, PP3, PP4, PP5
Fulgent Genetics, Fulgent Genetics	RCV000763520	SCV000894327	pathogenic	Adult polyglucosan body disease; Glycogen storage disease, type IV	2022-03-29	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000020163	SCV001193775	pathogenic	Glycogen storage disease, type IV	2019-12-20	criteria provided, single submitter	clinical testing	NM_000158.3(GBE1):c.986A>C(Y329S) is classified as pathogenic in the context of GBE1-related disorders and may be associated with adult polyglucosan body disease. Sources cited for classification include the following: 25665141, 8613547, 26385640, 26199317 and 23607684. Classification of NM_000158.3(GBE1):c.986A>C(Y329S) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Undiagnosed Diseases Network, NIH	RCV000991160	SCV001245583	pathogenic	Adult polyglucosan body disease	2021-04-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000493505	SCV001248811	pathogenic	not provided	2017-04-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000020163	SCV001821397	pathogenic	Glycogen storage disease, type IV	2021-08-27	criteria provided, single submitter	clinical testing	Variant summary: GBE1 c.986A>C (p.Tyr329Ser) 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 0.00032 in 248464 control chromosomes (gnomAD). c.986A>C has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Adult Polyglucosan Body Disease (APBD) and Glycogen Storage Disease, Type IV (e.g. Bao_1996, Roe_2010, Mochel_2012). APBD occurs most frequently in patients of Ashkenazi Jewish origin due to partial deficiency of the glycogen brancher enzyme, which is most commonly caused by the p.Tyr329Ser mutation (Roe_2010). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated the variant results in protein destabilization and in reduced enzyme activity compared to wild-type (Bao_1996, Akman_2015, Froese_2015). Eleven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000493505	SCV002024211	pathogenic	not provided	2022-01-09	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000991160	SCV002097106	pathogenic	Adult polyglucosan body disease	2022-01-27	criteria provided, single submitter	curation	The p.Tyr329Ser variant in GBE1 has been reported in many individuals with GBE1-related disorders (PMID: 8613547, 9851430, 20655781, 23034915, 25133958, 25665141, 33332610), segregated with disease in 4 affected relatives from 3 families (PMID: 9851430, 20655781, 33332610), and has been identified in 0.6% (65/10038) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (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#: 2777) and has been interpreted as pathogenic by multiple submitters in ClinVar. Of the many affected individuals, at least 2 of those were homozygotes, which increases the likelihood that the p.Tyr329Ser variant is pathogenic (PMID: 8613547, 9851430, 20655781, 23034915, 25133958, 25665141, 33332610). Animal models in mice have shown that this variant causes GBE1-related disorders (PMID: 26385640). Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive GBE1-related disorder. ACMG/AMP Criteria applied: PP3, PM3, PP1_strong, PS3 (Richards 2015).
Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center	RCV000991160	SCV004190169	pathogenic	Adult polyglucosan body disease	2021-07-12	criteria provided, single submitter	clinical testing	The variant in the GBE1 gene, c.986A>C is a missense variant, resulting in a tyrosine to serine protein substitution at position 329 (p.Tyr329Ser). This variant localizes to coding exon 7 of the GBE1 gene (16 exons in total; NM_000158.4) and is predicted to damage protein structure and/or function based on in silico analyses (Provean and SIFT). Functional studies show the expression of the recombinant protein carrying the p.Tyr329Ser variant results in drastically reduced protein yield and solubility, suggesting that the variant leads to protein misfolding (PMID: 26199317). The variant has also been shown to result in decreased enzyme activity ranging from undetectable levels to 50% of wild type (PMID: 8613547). This variant has been reported in several studies in either a homozygous or compound heterozygous state with a second known pathogenic variant in unrelated individuals with glycogen storage disease type IV or adult polyglucosan body disease (PMID: 9851430; 20655781; 22106711; 23034915; 25665141; 28265589; 32455116). It is also the most common variant associated with adult polyglucosan body disease in the Ashkenazi Jewish population (PMID: 25665141). This variant is reported in the Genome Aggregation Database (gnomAD) with an allele frequency of 79/248464 (no homozygote), indicating it is not a common benign variant in the populations represented in this database. It has already been interpreted as pathogenic by multiple laboratories in the ClinVar database (variation ID: 2777).
Baylor Genetics	RCV000020163	SCV004198658	pathogenic	Glycogen storage disease, type IV	2024-03-25	criteria provided, single submitter	clinical testing
OMIM	RCV000002907	SCV000023065	pathogenic	Glycogen storage disease IV, nonprogressive hepatic	1998-12-01	no assertion criteria provided	literature only
GeneReviews	RCV000020163	SCV000040490	not provided	Glycogen storage disease, type IV		no assertion provided	literature only
OMIM	RCV000150105	SCV000196929	pathogenic	Adult polyglucosan body neuropathy	1998-12-01	no assertion criteria provided	literature only
Reproductive Health Research and Development, BGI Genomics	RCV000991160	SCV001142329	pathogenic	Adult polyglucosan body disease	2020-01-06	no assertion criteria provided	curation	NM_000158.3:c.986A>C in the GBE1 gene has an allele frequency of 0.006 in Ashkenazi Jewish subpopulation in the gnomAD database. The c.986A>C (p.Tyr329Ser) missense variant has been reported in multiple individuals with glycogen storage disease type IV or adult polyglucosan body disease, both in homozygous state and compound heterozygous state: p.Y329S/p.L224P, p.Y329S/p.R565Q, p.Y329S/c.2003delA, p.Y329C/p.N556Y (PMID: 20655781; 23034915). Functional studies showed the Y329S variant has 50% of GBE activity when compared to wild type (PMID: 8613547). Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PS3, PM3_Strong, PP4.
Natera, Inc.	RCV000020163	SCV001461485	pathogenic	Glycogen storage disease, type IV	2020-09-16	no assertion criteria provided	clinical testing