NM_000152.5(GAA):c.716del (p.Leu239fs) AND Glycogen storage disease, type II

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Sep 20, 2020
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000672913.10

Allele description [Variation Report for NM_000152.5(GAA):c.716del (p.Leu239fs)]

NM_000152.5(GAA):c.716del (p.Leu239fs)

Gene:

GAA:alpha glucosidase [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

17q25.3

Genomic location:

Preferred name:

NM_000152.5(GAA):c.716del (p.Leu239fs)

HGVS:

NC_000017.11:g.80107580del
NG_009822.1:g.11025del
NM_000152.5:c.716delMANE SELECT
NM_001079803.3:c.716del
NM_001079804.3:c.716del
NP_000143.2:p.Leu239fs
NP_001073271.1:p.Leu239fs
NP_001073272.1:p.Leu239fs
LRG_673t1:c.716del
LRG_673:g.11025del
NC_000017.10:g.78081379del
NM_000152.3:c.716del
NM_000152.3:c.716delT
NM_000152.5(GAA):c.716delMANE SELECT
p.Leu239fs

Protein change:

L239fs

Links:

dbSNP: rs1555599594

NCBI 1000 Genomes Browser:

rs1555599594

Molecular consequence:

NM_000152.5:c.716del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001079803.3:c.716del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001079804.3:c.716del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Glycogen storage disease, type II (GSD2)
Synonyms:: ACID ALPHA-GLUCOSIDASE DEFICIENCY; GLYCOGENOSIS, GENERALIZED, CARDIAC FORM; GSD II; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009290; MedGen: C0017921; Orphanet: 365; OMIM: 232300

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000798068	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Feb 21, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001142800	Hadassah Hebrew University Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 20, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001418830	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 17, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 14695532, 18425781, 22252923, 28492532
SCV001443323	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	reviewed by expert panel (ClinGen LSD ACMG Specifications v1)	Pathogenic (Sep 20, 2020)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link

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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	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

Twenty-two novel mutations in the lysosomal alpha-glucosidase gene (GAA) underscore the genotype-phenotype correlation in glycogen storage disease type II.

Hermans MM, van Leenen D, Kroos MA, Beesley CE, Van Der Ploeg AT, Sakuraba H, Wevers R, Kleijer W, Michelakakis H, Kirk EP, Fletcher J, Bosshard N, Basel-Vanagaite L, Besley G, Reuser AJ.

Hum Mutat. 2004 Jan;23(1):47-56.

PubMed [citation]

PMID:: 14695532

See all PubMed Citations (6)

Details of each submission

From Counsyl, SCV000798068.1

#	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 Hadassah Hebrew University Medical Center, SCV001142800.2

#	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	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV001418830.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 556853). This premature translational stop signal has been observed in individual(s) with glycogen storage disease type II (PMID: 14695532). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu239Argfs*29) in the GAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923).

#	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 ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, SCV001443323.1

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

Description

This variant, c.716delT (p.Leu239ArgfsTer29), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. One patient with this variant meets the ClinGen LSD VCEP's specifications for PP4. This patient is compound heterozygous for the variant and c.1447G>A (p.Gly483Arg) (PMID 31606152, personal communication). This in trans data will be used in the assessment of p.Gly483Arg and is not included here in order to avoid circular logic. Another patient who is compound heterozygous for the variant has been reported (PMID 14695532). However, residual GAA activity was not provided and this data was not included. Therefore, PM3 is not currently met. This variant is not in gnomAD v2.1.1, meeting PM2. There is a ClinVar entry for this variant (Variation ID: 556853, 2 star review status) with one submitter classifying the variant as pathogenic and two as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PP4.

#	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: Mar 16, 2024

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