ClinVar Miner

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

gnomAD frequency: 0.00029  dbSNP: rs80338671
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Total submissions: 13
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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 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 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 2021-09-10 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 homozygotes. 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 carried a second variant (N556Y), phase of these variants is not specified (Mochel_2012). The variant has also been reported in additional glycogen storage disease patients in the literature, 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments: four classified as VUS while two classified as likely pathogenic. 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 Institute Rare Disease Group, Broad Institute 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 2022-07-01 criteria provided, single submitter clinical testing

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