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NM_000152.5(GAA):c.3G>A (p.Met1Ile) AND Glycogen storage disease, type II

Germline classification:
Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:
Oct 28, 2023
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV001249078.5

Allele description [Variation Report for NM_000152.5(GAA):c.3G>A (p.Met1Ile)]

NM_000152.5(GAA):c.3G>A (p.Met1Ile)

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.3G>A (p.Met1Ile)
HGVS:
  • NC_000017.11:g.80104589G>A
  • NG_009822.1:g.8034G>A
  • NM_000152.5:c.3G>AMANE SELECT
  • NM_001079803.3:c.3G>A
  • NM_001079804.3:c.3G>A
  • NP_000143.2:p.Met1Ile
  • NP_001073271.1:p.Met1Ile
  • NP_001073272.1:p.Met1Ile
  • LRG_673:g.8034G>A
  • NC_000017.10:g.78078388G>A
  • NC_000017.10:g.78078388G>A
  • NM_000152.4:c.3G>A
  • NM_001079804.2:c.3G>A
Protein change:
M1I
Links:
dbSNP: rs1187796945
NCBI 1000 Genomes Browser:
rs1187796945
Molecular consequence:
  • NM_000152.5:c.3G>A - initiator_codon_variant - [Sequence Ontology: SO:0001582]
  • NM_001079803.3:c.3G>A - initiator_codon_variant - [Sequence Ontology: SO:0001582]
  • NM_001079804.3:c.3G>A - initiator_codon_variant - [Sequence Ontology: SO:0001582]
  • NM_000152.5:c.3G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001079803.3:c.3G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001079804.3:c.3G>A - missense variant - [Sequence Ontology: SO:0001583]

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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001423033Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Jan 29, 2020) 		germlinecuration

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

Citation Link,

SCV001737739Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Likely pathogenic
(Jun 12, 2021) 		germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link,

SCV004297574Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Oct 28, 2023) 		germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, 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

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 (13)

Details of each submission

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001423033.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (1)

Description

The c.3G>A (p.Met1?) variant in GAA has been reported in at least three individuals with glycogen storage disease (PMID: 21803581, 18425781, 22252923, 22981821), and has been identified in 0.001% (1/111790) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1187796945). 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 located in the first amino acid of exon two and obliterates the methionine initiation codon. The next in-frame methionine is at amino acid residue 122 and there are at least seven reported pathogenic or likely pathogenic variants in ClinVar between amino acid 1 and amino acid 122. Proteins lacking this region are predicted to be extremely unstable (PMID: 22252923, 30192042, 22644586), suggesting that the c.3G>A variant may result in a truncated or absent protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive glycogen storage disease. In vitro functional studies provide some evidence that the p.Met1? variant may impact protein function (PMID: 18425781). However, these types of assays may not accurately represent biological function. Two additional likely pathogenic variants, resulting in a different amino acid change at the same position, c.1A>G and c.1A>T, have been reported in association with disease in the literature and ClinVar (PMID: 22252923, 30192042, 29889338, 28316933, 22644586; Variation ID: 188785). This variant was reported in combination with known pathogenic variants (VariationID: 4027, PMID: 22981821, 21803581, 22252923) and in individuals with glycogen storage disease. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PVS1_Strong (Richards 2015).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001737739.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

Variant summary: GAA c.3G>A (p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The next downstream putative in-frame start codon (Methionine) is located at p.Met122 in exon 2 of the GAA gene. The predicted truncated protein loses part of N-terminus of the encoded protein. Loss-of-function variants upstream of p.Met122 have been reported to be associated with Glycogen Storage Disease, Type 2 (example, p.R40*, p.Q115*, HGMD database). The variant allele was found at a frequency of 4e-06 in 247470 control chromosomes. c.3G>A has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) and has been subsequently cited by other studies due to authorship/institutional/patient overlap between studies (example, Kroos_2008, Yves Carlier_2011, Bali_2012, Desai_2019, Kishnani_2019, ElMallah_2020). Two additional likely pathogenic variants, resulting in a different amino acid change at the same position, c.1A>G and c.1A>T, have been reported in association with disease in the literature and the HGMD database. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV004297574.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This sequence change affects the initiator methionine of the GAA mRNA. The next in-frame methionine is located at codon 122. This variant is present in population databases (no rsID available, gnomAD 0.0009%). Disruption of the initiator codon has been observed in individual(s) with Pompe disease (PMID: 22252923, 29124014, 29422078, 31086307). ClinVar contains an entry for this variant (Variation ID: 972816). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects GAA function (PMID: 22644586, 31301153). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Mar 30, 2024