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NM_000152.5(GAA):c.701C>T (p.Thr234Met) AND Glycogen storage disease, type II

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Jan 15, 2024
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV001832749.5

Allele description [Variation Report for NM_000152.5(GAA):c.701C>T (p.Thr234Met)]

NM_000152.5(GAA):c.701C>T (p.Thr234Met)

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.701C>T (p.Thr234Met)
HGVS:
  • NC_000017.11:g.80107565C>T
  • NG_009822.1:g.11010C>T
  • NM_000152.5:c.701C>TMANE SELECT
  • NM_001079803.3:c.701C>T
  • NM_001079804.3:c.701C>T
  • NP_000143.2:p.Thr234Met
  • NP_001073271.1:p.Thr234Met
  • NP_001073272.1:p.Thr234Met
  • LRG_673t1:c.701C>T
  • LRG_673:g.11010C>T
  • NC_000017.10:g.78081364C>T
  • NM_000152.3:c.701C>T
Protein change:
T234M
Links:
dbSNP: rs752054011
NCBI 1000 Genomes Browser:
rs752054011
Molecular consequence:
  • NM_000152.5:c.701C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001079803.3:c.701C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001079804.3:c.701C>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
SCV002091953Natera, Inc.
no assertion criteria provided
Uncertain significance
(Mar 19, 2020) 		germlineclinical testing

SCV002152029Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jan 15, 2024) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Newborn screening for Pompe disease in Italy: Long-term results and future challenges.

Gragnaniello V, Pijnappel PWWM, Burlina AP, In 't Groen SLM, Gueraldi D, Cazzorla C, Maines E, Polo G, Salviati L, Di Salvo G, Burlina AB.

Mol Genet Metab Rep. 2022 Dec;33:100929. doi: 10.1016/j.ymgmr.2022.100929.

PubMed [citation]
PMID:
36310651
PMCID:
PMC9597184

Update of the pompe disease mutation database with 60 novel GAA sequence variants and additional studies on the functional effect of 34 previously reported variants.

Kroos M, Hoogeveen-Westerveld M, Michelakakis H, Pomponio R, Van der Ploeg A, Halley D, Reuser A; GAA Database Consortium..

Hum Mutat. 2012 Aug;33(8):1161-5. doi: 10.1002/humu.22108. Epub 2012 May 29.

PubMed [citation]
PMID:
22644586
See all PubMed Citations (5)

Details of each submission

From Natera, Inc., SCV002091953.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002152029.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 234 of the GAA protein (p.Thr234Met). This variant is present in population databases (rs752054011, gnomAD 0.003%). This missense change has been observed in individual(s) with Pompe disease (PMID: 36310651). ClinVar contains an entry for this variant (Variation ID: 1190471). 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 with a positive predictive value of 95%. This variant disrupts the p.Thr234 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22644586, 22676651, 34852371). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: Sep 29, 2024