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NM_000152.5(GAA):c.952A>T (p.Met318Leu) AND Glycogen storage disease, type II

Germline classification:
Likely pathogenic (2 submissions)
Last evaluated:
Aug 9, 2021
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:
RCV001379526.9

Allele description [Variation Report for NM_000152.5(GAA):c.952A>T (p.Met318Leu)]

NM_000152.5(GAA):c.952A>T (p.Met318Leu)

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.952A>T (p.Met318Leu)
HGVS:
  • NC_000017.11:g.80107893A>T
  • NG_009822.1:g.11338A>T
  • NM_000152.5:c.952A>TMANE SELECT
  • NM_001079803.3:c.952A>T
  • NM_001079804.3:c.952A>T
  • NP_000143.2:p.Met318Leu
  • NP_001073271.1:p.Met318Leu
  • NP_001073272.1:p.Met318Leu
  • LRG_673:g.11338A>T
  • NC_000017.10:g.78081692A>T
Protein change:
M318L
Links:
dbSNP: rs886044506
NCBI 1000 Genomes Browser:
rs886044506
Molecular consequence:
  • NM_000152.5:c.952A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001079803.3:c.952A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001079804.3:c.952A>T - 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
SCV001577338Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Aug 9, 2021) 		germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV001810529Genome-Nilou Lab
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Jul 22, 2021) 		germlineclinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

Identification of a missense mutation in one allele of a patient with Pompe disease, and use of endonuclease digestion of PCR-amplified RNA to demonstrate lack of mRNA expression from the second allele.

Zhong N, Martiniuk F, Tzall S, Hirschhorn R.

Am J Hum Genet. 1991 Sep;49(3):635-45.

PubMed [citation]
PMID:
1652892
PMCID:
PMC1683123

The pharmacological chaperone 1-deoxynojirimycin increases the activity and lysosomal trafficking of multiple mutant forms of acid alpha-glucosidase.

Flanagan JJ, Rossi B, Tang K, Wu X, Mascioli K, Donaudy F, Tuzzi MR, Fontana F, Cubellis MV, Porto C, Benjamin E, Lockhart DJ, Valenzano KJ, Andria G, Parenti G, Do HV.

Hum Mutat. 2009 Dec;30(12):1683-92. doi: 10.1002/humu.21121.

PubMed [citation]
PMID:
19862843
See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001577338.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Met318 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1652892, 19862843, 21484825, 29122469, 29181627). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GAA protein function. This sequence change replaces methionine with leucine at codon 318 of the GAA protein (p.Met318Leu). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and leucine. ClinVar contains an entry for this variant (Variation ID: 290616). This variant has not been reported in the literature in individuals affected with GAA-related conditions. This variant is not present in population databases (ExAC no frequency).

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

From Genome-Nilou Lab, SCV001810529.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenonot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024