NM_000152.5(GAA):c.1075G>T (p.Gly359Ter) AND Glycogen storage disease, type II

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 5, 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:: RCV001231709.11

Allele description [Variation Report for NM_000152.5(GAA):c.1075G>T (p.Gly359Ter)]

NM_000152.5(GAA):c.1075G>T (p.Gly359Ter)

Gene:

GAA:alpha glucosidase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q25.3

Genomic location:

Preferred name:

NM_000152.5(GAA):c.1075G>T (p.Gly359Ter)

HGVS:

NC_000017.11:g.80108409G>T
NG_009822.1:g.11854G>T
NM_000152.5:c.1075G>TMANE SELECT
NM_001079803.3:c.1075G>T
NM_001079804.3:c.1075G>T
NP_000143.2:p.Gly359Ter
NP_001073271.1:p.Gly359Ter
NP_001073272.1:p.Gly359Ter
LRG_673t1:c.1075G>T
LRG_673:g.11854G>T
NC_000017.10:g.78082208G>T
NM_000152.3:c.1075G>T
NM_000152.5(GAA):c.1075G>TMANE SELECT
p.Gly359Ter

Protein change:

G359*

Links:

dbSNP: rs1064794288

NCBI 1000 Genomes Browser:

rs1064794288

Molecular consequence:

NM_000152.5:c.1075G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001079803.3:c.1075G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001079804.3:c.1075G>T - nonsense - [Sequence Ontology: SO:0001587]

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001404240	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 10, 2019)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 19775921, 18425781, 22252923, 28492532
SCV001443320	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	reviewed by expert panel (ClinGen LSD ACMG Specifications v1)	Pathogenic (Oct 5, 2020)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 29122469, 25741864 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001404240

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 10, 2019)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV001443320

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

reviewed by expert panel

(ClinGen LSD ACMG Specifications v1)

Pathogenic
(Oct 5, 2020)

germline

curation

PubMed (2)
[See all records that cite these PMIDs]

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

Citations

PubMed

Cross-reactive immunologic material status affects treatment outcomes in Pompe disease infants.

Kishnani PS, Goldenberg PC, DeArmey SL, Heller J, Benjamin D, Young S, Bali D, Smith SA, Li JS, Mandel H, Koeberl D, Rosenberg A, Chen YT.

Mol Genet Metab. 2010 Jan;99(1):26-33. doi: 10.1016/j.ymgme.2009.08.003.

PubMed [citation]

PMID:: 19775921
PMCID:: PMC3721340

Update of the Pompe disease mutation database with 107 sequence variants and a format for severity rating.

Kroos M, Pomponio RJ, van Vliet L, Palmer RE, Phipps M, Van der Helm R, Halley D, Reuser A; GAA Database Consortium..

Hum Mutat. 2008 Jun;29(6):E13-26. doi: 10.1002/humu.20745.

PubMed [citation]

PMID:: 18425781

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001404240.5

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

Description

This variant has been observed in an individual affected with Pompe disease (PMID: 19775921). ClinVar contains an entry for this variant (Variation ID: 420101). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gly359*) in the GAA gene. It is expected to result in an absent or disrupted protein product.

#	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, SCV001443320.1

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

Description

This variant, c.1075G>T (p.Gly359Ter), is predicted to result in a premature stop codon and nonsense-mediated decay, resulting in lack of gene product. Of note, the variant alters the last nucleotide of exon 6 and splicing predictors indicate that splicing may be impacted. The impact of a splicing defect, if it occurs, is not known. However, a patient with infantile onset Pompe disease who is homozygous for the variant has no GAA cross reactive immunological material in cultured skin fibroblasts i.e. CRIM-negative, indicating that the variant results in lack of GAA protein. Based on this data, PVS1 was applied. This patient, who has infantile onset Pompe disease, also has low residual GAA activity, meeting PP4, and is homozygous for the variant, meeting PM3_Supporting. The variant is absent in gnomAD v2.1.1 meeting PM2. There is a ClinVar entry for this variant (Variation ID: 420101, 2 star review status) with two submitters classifying the variant as 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, PM3_Supporting, 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: Sep 29, 2024

ClinVar

Relating variation to medicine