NM_000152.5(GAA):c.2655_2656del (p.Val886fs) AND Glycogen storage disease, type II

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 1, 2021
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:: RCV001789710.3

Allele description [Variation Report for NM_000152.5(GAA):c.2655_2656del (p.Val886fs)]

NM_000152.5(GAA):c.2655_2656del (p.Val886fs)

Gene:

GAA:alpha glucosidase [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

17q25.3

Genomic location:

Preferred name:

NM_000152.5(GAA):c.2655_2656del (p.Val886fs)

Other names:

NM_000152.5(GAA):c.2655_2656del; p.Val886fs

HGVS:

NC_000017.11:g.80118661_80118662del
NG_009822.1:g.22106_22107del
NM_000152.5:c.2655_2656delMANE SELECT
NM_001079803.3:c.2655_2656del
NM_001079804.3:c.2655_2656del
NP_000143.2:p.Val886fs
NP_001073271.1:p.Val886fs
NP_001073272.1:p.Val886fs
LRG_673:g.22106_22107del
NC_000017.10:g.78092460_78092461del

Protein change:

V886fs

Links:

dbSNP: rs1555603219

NCBI 1000 Genomes Browser:

rs1555603219

Molecular consequence:

NM_000152.5:c.2655_2656del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001079803.3:c.2655_2656del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001079804.3:c.2655_2656del - 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
SCV002032121	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	reviewed by expert panel (clingen_lsd_acmg_specifications_v2-1)	Pathogenic (Sep 1, 2021)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002032121

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

reviewed by expert panel

(clingen_lsd_acmg_specifications_v2-1)

Pathogenic
(Sep 1, 2021)

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

Details of each submission

From ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, SCV002032121.1

#	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.2655_2656del (p.Val886GlufsTer2) variant in GAA is a frameshift variant predicted to cause a premature stop codon and to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Two siblings with this variant and late-onset Pompe disease have been reported with GAA activity in dried blood spots below the normal range, and both are on enzyme replacement therapy (PMID 31392188, personal communication)(PP4_Moderate). These individuals are compound heterozygous for the variant and a pathogenic variant in GAA, c.-32-13T>G, phase unknown (PM3_Supporting). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 597005; 1 star review status) with one submitter 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 met, based on the specifications of the ClinGen LSD VCEP (Specifications Version 2.0): PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting.

#	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 1, 2023

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