ClinVar Miner

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

dbSNP: rs80338671
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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services,Illumina RCV000304728 SCV000446301 pathogenic GBE1-Related Disorders 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)
Invitae RCV000555363 SCV000626776 pathogenic Glycogen storage disease, type IV; Glycogen storage disease IV, classic hepatic 2020-10-31 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with serine at codon 329 of the GBE1 protein (p.Tyr329Ser). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and serine. This variant is present in population databases (rs80338671, ExAC 0.05%). This variant has been reported to be the most common cause of adult polyglucosan body disease in the Ashkenazi Jewish population (PMID: 8613547, 20655781, 24082139, 25133958, 25665141). ClinVar contains an entry for this variant (Variation ID: 2777). Experimental studies have shown that this missense change reduces GBE1 protein stability and enzymatic activity. Also, a mouse model expressing this variant has been reported to exhibit a phenotype similar to adult polyglucosan body disease (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 2018-10-31 criteria provided, single submitter clinical testing
Myriad Women's Health, 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.
Broad Institute Rare Disease Group, Broad Institute 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).
OMIM RCV000002907 SCV000023065 pathogenic Glycogen storage disease IV, nonprogressive hepatic 1998-12-01 no assertion criteria provided literature only
GeneReviews RCV000020163 SCV000040490 pathologic Glycogen storage disease, type IV 2009-04-02 no assertion criteria provided curation Converted during submission to Pathogenic.
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
PerkinElmer Genomics RCV000493505 SCV002024211 pathogenic not provided 2021-05-18 no assertion criteria provided clinical testing

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