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NM_000152.5(GAA):c.2238G>C (p.Trp746Cys) AND GAA-related disorder

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Aug 9, 2024
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
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:
RCV003920023.3

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

NM_000152.5(GAA):c.2238G>C (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>C (p.Trp746Cys)
Other names:
NM_000152.3(GAA):c.2238G>C(p.Trp746Cys); NM_001079803.1(GAA):c.2238G>C(p.Trp746Cys); NM_001079804.1(GAA):c.2238G>C(p.Trp746Cys)
HGVS:
  • NC_000017.11:g.80117016G>C
  • NG_009822.1:g.20461G>C
  • NM_000152.4(GAA):c.2238G>C
  • NM_000152.5:c.2238G>CMANE SELECT
  • NM_001079803.3:c.2238G>C
  • NM_001079804.3:c.2238G>C
  • NP_000143.2:p.Trp746Cys
  • NP_001073271.1:p.Trp746Cys
  • NP_001073272.1:p.Trp746Cys
  • LRG_673t1:c.2238G>C
  • LRG_673:g.20461G>C
  • NC_000017.10:g.78090815G>C
  • NM_000152.3:c.2238G>C
  • NM_000152.4(GAA):c.2238G>C
  • NM_000152.4:c.2238G>C
  • NM_001079803.1:c.2238G>C
  • NM_001079803.2:c.2238G>C
  • NM_001079804.3:c.2238G>C
  • P10253:p.Trp746Cys
Protein change:
W746C
Links:
UniProtKB: P10253#VAR_004311; dbSNP: rs1800312
NCBI 1000 Genomes Browser:
rs1800312
Molecular consequence:
  • NM_000152.5:c.2238G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001079803.3:c.2238G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001079804.3:c.2238G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
GAA-related disorder
Synonyms:
GAA-related condition
Identifiers:

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004729428PreventionGenetics, part of Exact Sciences
no assertion criteria provided
Pathogenic
(Aug 9, 2024) 		germlineclinical testing

Help

Summary from all submissions

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

Details of each submission

From PreventionGenetics, part of Exact Sciences, SCV004729428.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The GAA c.2238G>C variant is predicted to result in the amino acid substitution p.Trp746Cys. This variant has been reported, in the homozygous or compound heterozygous state, in numerous glycogen storage disease type II (GSD II) patients. In most cases, it has been associated with late-onset/juvenile-onset GSD II (e.g., Wan et al. 2008. PubMed ID: 18458862; Chien et al. 2011. PubMed ID: 21232767; Liu et al. 2018. PubMed ID: 29451150). It has been reported to be the most common late-onset Pompe disease (LOPD) variant among the mainland Chinese population (Liu et al. 2014. PubMed ID: 25526786). In functional studies, the p.Trp746Cys substitution has been reported to reduce GAA enzyme activity to ~5-10% of wild-type, and is typically considered a mild variant based on this level of residual enzyme activity (Huie et al. 1998. PubMed ID: 9535769; Yang et al. 2011. PubMed ID: 21757382; Niño et al. 2013. PubMed ID: 23430493). This variant is reported in 0.057% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Different substitutions of the same amino acid (p.Trp746Arg, p.Trp746Gly, p.Trp746Ser) have also been reported in association with GSD II (Human Gene Mutation Database). The c.2238G>C (p.Trp746Cys) variant is interpreted as pathogenic.

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

Last Updated: Oct 20, 2024