NM_000152.5(GAA):c.2544del (p.Lys849fs) AND Glycogen storage disease, type II

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Dec 2, 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:: RCV001249089.8

Allele description [Variation Report for NM_000152.5(GAA):c.2544del (p.Lys849fs)]

NM_000152.5(GAA):c.2544del (p.Lys849fs)

Gene:

GAA:alpha glucosidase [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

17q25.3

Genomic location:

Preferred name:

NM_000152.5(GAA):c.2544del (p.Lys849fs)

Other names:

NM_000152.5(GAA):c.2544del; p.Lys849fs

HGVS:

NC_000017.11:g.80118255del
NG_009822.1:g.21700del
NM_000152.5:c.2544delMANE SELECT
NM_001079803.3:c.2544del
NM_001079804.3:c.2544del
NP_000143.2:p.Lys849fs
NP_001073271.1:p.Lys849fs
NP_001073272.1:p.Lys849fs
LRG_673t1:c.2544del
LRG_673:g.21700del
NC_000017.10:g.78092054del
NC_000017.11:g.80118255delC
NM_000152.3:c.2544delC
NM_000152.4(GAA):c.2544delC
p.Lys849Argfs

Protein change:

K849fs

Links:

dbSNP: rs398123173

NCBI 1000 Genomes Browser:

rs398123173

Molecular consequence:

NM_000152.5:c.2544del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001079803.3:c.2544del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001079804.3:c.2544del - 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

Recent activity

Clear Turn Off Turn On

Halichoeres garnoti large subunit ribosomal RNA gene, partial sequence; mitochon...
Halichoeres garnoti large subunit ribosomal RNA gene, partial sequence; mitochondrial
gi|2430236228|gb|OQ303707.1|

Nucleotide
Ballerus ballerus voucher Bba01 large subunit ribosomal RNA gene, partial sequen...
Ballerus ballerus voucher Bba01 large subunit ribosomal RNA gene, partial sequence; mitochondrial
gi|1699951031|gb|MN153576.1|

Nucleotide

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
SCV001423059	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 22, 2020)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV002032118	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	reviewed by expert panel (clingen_lsd_acmg_specifications_v2-1)	Pathogenic (Dec 2, 2021)	germline	curation	Citation Link,
SCV004195475	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 21, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001423059

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 22, 2020)

germline

curation

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

Citation Link,

SCV002032118

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

reviewed by expert panel

(clingen_lsd_acmg_specifications_v2-1)

Pathogenic
(Dec 2, 2021)

germline

curation

Citation Link,

SCV004195475

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 21, 2023)

unknown

clinical testing

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

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 Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001423059.2

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

Description

The p.Lys849ArgfsTer38 variant in GAA has been reported in 1 individual with Glycogen Storage Disease II (DOI: 10.1186/1471-2474-14-S2-P3), and has also been reported pathogenic by EGL in ClinVar (Variation ID: 92480). This variant has been identified in 0.0009% (1/112244) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs398123173). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 849 and leads to a premature termination codon 38 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive Glycogen Storage Disease II. This variant was seen in combination with a complex deletion and in an individual with Glycogen Storage Disease II (DOI: 10.1186/1471-2474-14-S2-P3). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2 (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

From ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, SCV002032118.1

#	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.2544del (p.Lys849ArgfsTer38) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 19/20. Although the premature stop codon is thought to occur in the penultimate exon of the gene, it is not within the last 50 base pairs of the exon and, therefore, it is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. A patient with this variant has been reported to have no GAA cross-reactive material (CRIM-negative)(PMID 23763753), supporting that this variant is a loss of function variant (PVS1). This patient, who has symptoms consistent with infantile onset Pompe disease, and another individual with late-onset Pompe disease and documented laboratory values showing deficient GAA activity (PMID 30363678), both meet the ClinGen LSD VCEP’s specifications for PP4_Moderate. The first patient (CRIM-negative) is compound heterozygous for the variant and a "complex deletion". Because details of the complex deletion are unavailable, this data was not included for PM3. The second patient is compound heterozygous for the variant and a pathogenic variant in GAA, c.-32-13T>G, phase unknown (PMID: 30363678)(0.5 points, PM3_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000009 in the European non-Finnish population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 92480, one star review status) with one submitter classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by 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

From Baylor Genetics, SCV004195475.1

#	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

Last Updated: Jun 23, 2024

ClinVar

Relating variation to medicine