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NM_000158.4(GBE1):c.986A>G (p.Tyr329Cys) AND Glycogen storage disease, type IV

Germline classification:
Conflicting interpretations of pathogenicity (9 submissions)
Last evaluated:
Mar 26, 2024
Review status:
criteria provided, conflicting classifications
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000410814.28

Allele description [Variation Report for NM_000158.4(GBE1):c.986A>G (p.Tyr329Cys)]

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

Gene:
GBE1:1,4-alpha-glucan branching enzyme 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
3p12.2
Genomic location:
Preferred name:
NM_000158.4(GBE1):c.986A>G (p.Tyr329Cys)
Other names:
NM_000158.4(GBE1):c.986A>G; p.Tyr329Cys
HGVS:
  • NC_000003.12:g.81642787T>C
  • NG_011810.1:g.124014A>G
  • NM_000158.4:c.986A>GMANE SELECT
  • NP_000149.4:p.Tyr329Cys
  • NC_000003.11:g.81691938T>C
  • NM_000158.3:c.986A>G
Protein change:
Y329C
Links:
dbSNP: rs80338671
NCBI 1000 Genomes Browser:
rs80338671
Molecular consequence:
  • NM_000158.4:c.986A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Glycogen storage disease, type IV (GSD4)
Synonyms:
GBE1 DEFICIENCY; GLYCOGENOSIS IV; GSD IV; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0009292; MedGen: C0017923; Orphanet: 367; OMIM: 232500

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000487021Counsyl
criteria provided, single submitter

(Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))
Likely pathogenic
(Oct 31, 2016)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf,

Citation Link,

SCV001305737Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)
Uncertain significance
(Apr 27, 2017)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV001338529Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Likely pathogenic
(Mar 15, 2024)
germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

Citation Link,

SCV001810439Genome-Nilou Lab
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Jul 22, 2021)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002097105Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Jan 27, 2022)
germlinecuration

PubMed (1)
[See all records that cite this PMID]

SCV002557032Genetics and Molecular Pathology, SA Pathology

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(May 26, 2021)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004198699Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Jul 15, 2023)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004806797Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Mar 26, 2024)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV005042802Neuberg Centre For Genomic Medicine, NCGM
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significancegermlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenonot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, curation
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Hepatic and neuromuscular forms of glycogen storage disease type IV caused by mutations in the same glycogen-branching enzyme gene.

Bao Y, Kishnani P, Wu JY, Chen YT.

J Clin Invest. 1996 Feb 15;97(4):941-8.

PubMed [citation]
PMID:
8613547
PMCID:
PMC507139

Mini-Exome Coupled to Read-Depth Based Copy Number Variation Analysis in Patients with Inherited Ataxias.

Marelli C, Guissart C, Hubsch C, Renaud M, Villemin JP, Larrieu L, Charles P, Ayrignac X, Sacconi S, Collignon P, Cuntz-Shadfar D, Perrin L, Benarrosh A, Degardin A, Lagha-Boukbiza O, Mutez E, Carlander B, Morales RJ, Gonzalez V, Carra-Dalliere C, Azakri S, Mignard C, et al.

Hum Mutat. 2016 Dec;37(12):1340-1353. doi: 10.1002/humu.23063. Epub 2016 Sep 2.

PubMed [citation]
PMID:
27528516
See all PubMed Citations (11)

Details of each submission

From Counsyl, SCV000487021.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Illumina Laboratory Services, Illumina, SCV001305737.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001338529.8

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

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 homozygotes. This frequency is not significantly higher than estimated 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) (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. The following publications have been ascertained in the context of this evaluation (PMID: 31207142, 31980526, 31209396, 31319225, 34426522, 27528516, 23034915, 30293248, 28716262). ClinVar contains an entry for this variant (Variation ID: 371439). Based on the evidence outlined above, the variant was classified as likely pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Genome-Nilou Lab, SCV001810439.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenonot providednot providednot providednot providednot providednot providednot provided

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV002097105.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (1)

Description

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).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Genetics and Molecular Pathology, SA Pathology, SCV002557032.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Baylor Genetics, SCV004198699.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004806797.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV005042802.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

The missense c.986A>G p.Tyr329Cys variant in the GBE1 gene has been reported in 6 individuals with GBE1-related disorders Nair, Pratibha et al., 2018. This variant is reported with the allele frequency 0.04% in the gnomAD Exomes and novel in 1000 Genomes. It is submitted to ClinVar as Likely Pathogenic/ Uncertain Significance multiple submissions. The amino acid Tyrosine at position 329 is changed to a Cysteine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Tyr329Cys in GBE1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 15, 2024