NM_000158.4(GBE1):c.760A>G (p.Thr254Ala) AND Glycogen storage disease, type IV

Germline classification:: Conflicting interpretations of pathogenicity (6 submissions)
Last evaluated:: Mar 30, 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:: RCV001147053.15

Allele description [Variation Report for NM_000158.4(GBE1):c.760A>G (p.Thr254Ala)]

NM_000158.4(GBE1):c.760A>G (p.Thr254Ala)

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.760A>G (p.Thr254Ala)

Other names:

NM_000158.4(GBE1):c.760A>G; p.Thr254Ala

HGVS:

NC_000003.12:g.81646414T>C
NG_011810.1:g.120387A>G
NM_000158.4:c.760A>GMANE SELECT
NP_000149.4:p.Thr254Ala
NC_000003.11:g.81695565T>C
NM_000158.3:c.760A>G

Protein change:

T254A

Links:

dbSNP: rs770427750

NCBI 1000 Genomes Browser:

rs770427750

Molecular consequence:

NM_000158.4:c.760A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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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Homo sapiens NKAP domain containing 1 (NKAPD1), transcript variant 7, mRNA
Homo sapiens NKAP domain containing 1 (NKAPD1), transcript variant 7, mRNA
gi|1675031757|ref|NM_001301021.2|

Nucleotide
POU domain, class 2, transcription factor 1 isoform L [Mus musculus]
POU domain, class 2, transcription factor 1 isoform L [Mus musculus]
gi|114431256|ref|NP_945151.2|

Protein
Synthetic construct Homo sapiens clone IMAGE:100068247, MGC:195864 arginine-glut...
Synthetic construct Homo sapiens clone IMAGE:100068247, MGC:195864 arginine-glutamic acid dipeptide (RE) repeats (RERE) mRNA, encodes complete protein
gi|189442425|gb|BC167857.1|

Nucleotide
Chain A, Hemoglobin subunit alpha
Chain A, Hemoglobin subunit alpha
gi|168988854|pdb|2ZFB|A

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001307825	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 27, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 20058079, 27107456 Citation Link,
SCV002082387	Natera, Inc.	no assertion criteria provided	Uncertain significance (Apr 2, 2021)	germline	clinical testing
SCV002097116	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 27, 2022)	germline	curation	PubMed (1) [See all records that cite this PMID]
SCV002581806	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 22, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004198660	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 30, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005091243	Solve-RD Consortium	no assertion criteria provided	Likely pathogenic (Jun 1, 2022)	inherited	provider interpretation

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	inherited	yes	not provided	not provided	not provided	not provided	not provided	provider interpretation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Glycogen storage disease type IV: novel mutations and molecular characterization of a heterogeneous disorder.

Li SC, Chen CM, Goldstein JL, Wu JY, Lemyre E, Burrow TA, Kang PB, Chen YT, Bali DS.

J Inherit Metab Dis. 2010 Dec;33 Suppl 3:S83-90. doi: 10.1007/s10545-009-9026-5. Epub 2010 Jan 8.

PubMed [citation]

PMID:: 20058079

A novel GBE1 gene variant in a child with glycogen storage disease type IV.

Said SM, Murphree MI, Mounajjed T, El-Youssef M, Zhang L.

Hum Pathol. 2016 Aug;54:152-6. doi: 10.1016/j.humpath.2016.03.021. Epub 2016 Apr 20.

PubMed [citation]

PMID:: 27107456

See all PubMed Citations (3)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV001307825.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV002082387.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV002097116.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (1)

Description

The p.Thr254Ala variant in GBE1 has been reported in 2 individuals with glycogen storage disease type IV (GSD IV) (PMID: 30569318), segregated with disease in 1 individual from 1 family (PMID: 33332610) and has been identified in 0.01% (13/111154) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs770427750). 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. Of the 3 affected individuals, 1 was a compound heterozygote that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Gly264Glu variant is pathogenic (VariationID: 208584; PMID: 30569318). This variant has also been reported in ClinVar (Variation ID#: 374517) and has been interpreted as likely pathogenic by CeGaT Praxis fuer Humangenetik Tuebingen, and as a variant of uncertain significance by Illumina Clinical Services Laboratory (Illumina), Invitae, GeneDx, and Women's Health and Genetics (Laboratory Corporation of America, LabCorp). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Thr254Ala variant is uncertain. ACMG/AMP Criteria applied: PP3, PM3 (Richards 2015).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From MGZ Medical Genetics Center, SCV002581806.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

From Baylor Genetics, SCV004198660.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Solve-RD Consortium, SCV005091243.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	provider interpretation	not provided

Description

Variant confirmed as disease-causing by referring clinical team

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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