NM_000152.5(GAA):c.1099del (p.Trp367fs) AND Glycogen storage disease, type II

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Mar 10, 2023
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:: RCV000410443.6

Allele description [Variation Report for NM_000152.5(GAA):c.1099del (p.Trp367fs)]

NM_000152.5(GAA):c.1099del (p.Trp367fs)

Gene:

GAA:alpha glucosidase [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

17q25.3

Genomic location:

Preferred name:

NM_000152.5(GAA):c.1099del (p.Trp367fs)

HGVS:

NC_000017.11:g.80108512del
NG_009822.1:g.11957del
NM_000152.5:c.1099delMANE SELECT
NM_001079803.3:c.1099del
NM_001079804.3:c.1099del
NP_000143.2:p.Trp367fs
NP_001073271.1:p.Trp367fs
NP_001073272.1:p.Trp367fs
LRG_673t1:c.1099del
LRG_673:g.11957del
NC_000017.10:g.78082311del
NM_000152.3:c.1099delT
NM_000152.5(GAA):c.1099delMANE SELECT
p.Trp367fs

Protein change:

W367fs

Links:

dbSNP: rs1057516785

NCBI 1000 Genomes Browser:

rs1057516785

Molecular consequence:

NM_000152.5:c.1099del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001079803.3:c.1099del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001079804.3:c.1099del - 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
SCV000486219	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Apr 20, 2016)	unknown	clinical testing	mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV001443327	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	reviewed by expert panel (clingen_lsd_acmg_specifications_v2-1)	Likely pathogenic (Mar 10, 2023)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000486219

Counsyl

criteria provided, single submitter

(Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))

Likely pathogenic
(Apr 20, 2016)

unknown

clinical testing

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

Citation Link,

SCV001443327

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

reviewed by expert panel

(clingen_lsd_acmg_specifications_v2-1)

Likely pathogenic
(Mar 10, 2023)

germline

curation

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	curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From Counsyl, SCV000486219.2

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, SCV001443327.2

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

Description

The NM_000152.5:c.1099del (p.Trp367GlyfsTer25) variant in GAA is a nonsense variant predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is not in gnomAD v2.1.1. ( PM2_Supporting). To our knowledge, this variant has not been reported in patients with Pompe disease in the literature, and results of functional studies are not available. There is a ClinVar entry for this variant (Variation ID: 370810). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PVS1, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP, March 10, 2023).

#	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: Apr 9, 2023

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