NM_000158.4(GBE1):c.721A>G (p.Met241Val) AND Glycogen storage disease, type IV

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jan 27, 2022
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:: RCV000329970.10

Allele description [Variation Report for NM_000158.4(GBE1):c.721A>G (p.Met241Val)]

NM_000158.4(GBE1):c.721A>G (p.Met241Val)

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.721A>G (p.Met241Val)

Other names:

NM_000158.4(GBE1):c.721A>G; p.Met241Val

HGVS:

NC_000003.12:g.81646453T>C
NG_011810.1:g.120348A>G
NM_000158.4:c.721A>GMANE SELECT
NP_000149.4:p.Met241Val
NC_000003.11:g.81695604T>C
NC_000003.11:g.81695604T>C
NM_000158.3:c.721A>G

Protein change:

M241V

Links:

dbSNP: rs747155575

NCBI 1000 Genomes Browser:

rs747155575

Molecular consequence:

NM_000158.4:c.721A>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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Mus musculus T-box 21 (Tbx21), mRNA
Mus musculus T-box 21 (Tbx21), mRNA
gi|9507178|ref|NM_019507.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000446307	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Jan 13, 2018)	germline	clinical testing	Citation Link,
SCV001478066	Institute of Human Genetics, University of Goettingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 23, 2021)	maternal	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002097117	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]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000446307

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Jan 13, 2018)

germline

clinical testing

Citation Link,

SCV001478066

Institute of Human Genetics, University of Goettingen

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 23, 2021)

maternal

clinical testing

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

SCV002097117

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]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	maternal	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000446307.3

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

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

#	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 Institute of Human Genetics, University of Goettingen, SCV001478066.1

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

Description

The GBE1 variant c.721A>G (p.(Met241Val)) is found at a population frequency of 0.0029% in the gnomAD database, it affects a highly conserved nucleotide and a highly conserved amino acid and there is a small physicochemical difference between Met and Val. It is located within a protein domain and has a pathogenic computational verdict based on in silico prediction programs (M-CAP, SIFT, MutationTaster, PolyPhen-2). In our clinic this variant was found in compound-heterozygosity with the splice site variant c.691+2T>C (dbSNP: rs192044702), which is known to cause Glycogen storage disease type IV (OMIM: 232500) when in homozygous or compound heterozygous state. Thus, we consider the c.721A>G variant to be likely pathogenic. ACMG criteria used for classification: PM1, PM2, PM3, PP2, PP3.

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

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV002097117.1

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

Description

The p.Met241Val variant in GBE1 has been reported in 1 individual, in the compound heterozygous state, with glycogen storage disease type IV (GSD IV) (ClinVar Variation ID: 346793) and has been identified in 0.005% (6/110798) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs781198373). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 346793) and has been interpreted as likely pathogenic by Clinical Genetics laboratory (University of Goettingen). 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.Met241Val variant is uncertain. ACMG/AMP Criteria applied: PM3, PP3, PM2_supporting (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

Last Updated: Nov 3, 2024

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