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NM_000152.5(GAA):c.2238G>T (p.Trp746Cys) AND Glycogen storage disease, type II

Germline classification:
Pathogenic (1 submission)
Last evaluated:
May 8, 2022
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:
RCV002745939.3

Allele description [Variation Report for NM_000152.5(GAA):c.2238G>T (p.Trp746Cys)]

NM_000152.5(GAA):c.2238G>T (p.Trp746Cys)

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.2238G>T (p.Trp746Cys)
HGVS:
  • NC_000017.11:g.80117016G>T
  • NG_009822.1:g.20461G>T
  • NM_000152.5:c.2238G>TMANE SELECT
  • NM_001079803.3:c.2238G>T
  • NM_001079804.3:c.2238G>T
  • NM_001406741.1:c.2238G>T
  • NM_001406742.1:c.2238G>T
  • NP_000143.2:p.Trp746Cys
  • NP_000143.2:p.Trp746Cys
  • NP_001073271.1:p.Trp746Cys
  • NP_001073272.1:p.Trp746Cys
  • NP_001393670.1:p.Trp746Cys
  • NP_001393671.1:p.Trp746Cys
  • LRG_673t1:c.2238G>T
  • LRG_673:g.20461G>T
  • LRG_673p1:p.Trp746Cys
  • NC_000017.10:g.78090815G>T
  • NM_000152.3:c.2238G>T
Protein change:
W746C
Molecular consequence:
  • NM_000152.5:c.2238G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001079803.3:c.2238G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001079804.3:c.2238G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406741.1:c.2238G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406742.1:c.2238G>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
SCV003015113Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(May 8, 2022) 		germlineclinical testing

PubMed (8)
[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

Identification of eight novel mutations of the acid alpha-glucosidase gene causing the infantile or juvenile form of glycogen storage disease type II.

Wan L, Lee CC, Hsu CM, Hwu WL, Yang CC, Tsai CH, Tsai FJ.

J Neurol. 2008 Jun;255(6):831-8. doi: 10.1007/s00415-008-0714-0. Epub 2008 May 6.

PubMed [citation]
PMID:
18458862

Later-onset Pompe disease: early detection and early treatment initiation enabled by newborn screening.

Chien YH, Lee NC, Huang HJ, Thurberg BL, Tsai FJ, Hwu WL.

J Pediatr. 2011 Jun;158(6):1023-1027.e1. doi: 10.1016/j.jpeds.2010.11.053. Epub 2011 Jan 13.

PubMed [citation]
PMID:
21232767
See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003015113.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 746 of the GAA protein (p.Trp746Cys). This variant is not present in population databases (gnomAD no frequency). A different variant (c.2238G>C) giving rise to the same protein effect has been determined to be pathogenic (PMID: 18458862, 21232767, 21757382, 23430493, 25093132, 25526786, 27099502). This suggests that this variant is also likely to be causative of disease. 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. 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