ClinVar Miner

Submissions for variant NM_000158.4(GBE1):c.986A>G (p.Tyr329Cys) (rs80338671)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
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 2018-01-04 criteria provided, single submitter clinical testing The Y329C variant in the GBE1 gene has been reported previously in five individuals with adult polyglucosan body disease who harbored a second missense variant (N556Y), phase of these variants is not described, and were reported to have reduced GBE enzymatic activity (Mochel et al., 2012). Another missense variant at the same codon (Y329S) is commonly observed within affected Ashkenazi Jews (Mochel et al., 2012); enzymatic studies of this other variant (Y329S) have shown a reduction in GBE enzymatic activity (Bao et al., 1996). However, the Y329C variant is observed in 13/16490 (0.08%) alleles from individuals of south Asian background in the ExAC dataset (Lek et al., 2016) and is present in 3 presumably healthy homozygous individuals tested at GeneDx. The Y329C variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret Y329C as a variant of uncertain significance.
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 2020-10-26 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 329 of the GBE1 protein (p.Tyr329Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs80338671, ExAC 0.08%). This variant has been reported in five individuals affected with adult polyglucosan body disease in combination with another GBE1 variant (p.Asn556Tyr). However, the phase of these variants has not been resolved (PMID: 23034915). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different missense substitution at this codon (p.Tyr329Ser) has been determined to be pathogenic (PMID: 8613547, 25665141, 26199317, 26385640). This suggests that the tyrosine residue is critical for GBE1 protein function and that other missense substitutions at this position may also be pathogenic. 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 Clinical Services Laboratory,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 Clinical Services Laboratory,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 2020-04-17 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 in the gnomAD database, including 1 homozygote. This frequency is not 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 individuals affected with Adult Polyglucosan Body Disease who carried a second variant (N556Y), phase of these variants is not specified (Mochel_2012). 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. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (1x), likely pathogenic (2x) and pathogenic (1x). Based on the evidence outlined above, the variant was classified as likely pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.