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NM_000152.5(GAA):c.2297A>G (p.Tyr766Cys)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely pathogenic(3);Pathogenic(1);Uncertain significance(2)

Review status:
criteria provided, conflicting interpretations
Submissions:
8 (Most recent: Nov 19, 2021)
Last evaluated:
Jul 22, 2021
Accession:
VCV000285197.10
Variation ID:
285197
Description:
single nucleotide variant
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NM_000152.5(GAA):c.2297A>G (p.Tyr766Cys)

Allele ID
269434
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
17q25.3
Genomic location
17: 80117075 (GRCh38) GRCh38 UCSC
17: 78090874 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
LRG_673t1:c.2297A>G
LRG_673:g.20520A>G
P10253:p.Tyr766Cys
... more HGVS
Protein change
Y766C
Other names
-
Canonical SPDI
NC_000017.11:80117074:A:G
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
The Genome Aggregation Database (gnomAD) 0.00003
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Links
ClinGen: CA8815679
UniProtKB: P10253#VAR_070019
dbSNP: rs144016984
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Conflicting interpretations of pathogenicity 3 criteria provided, conflicting interpretations Jun 30, 2021 RCV000403113.4
Conflicting interpretations of pathogenicity 5 criteria provided, conflicting interpretations Jul 22, 2021 RCV001049848.6
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
GAA - - GRCh38
GRCh37
1548 1588

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Uncertain significance
(Jan 04, 2016)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics
Accession: SCV000338123.4
Submitted: (Sep 19, 2018)
Evidence details
Other databases
http://www.egl-eurofins.com/emvc…
Uncertain significance
(Apr 28, 2017)
criteria provided, single submitter
Method: clinical testing
Glycogen storage disease, type II
Allele origin: germline
Illumina Clinical Services Laboratory,Illumina
Accession: SCV001281478.1
Submitted: (Feb 20, 2020)
Evidence details
Publications
PubMed (2)
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
Likely pathogenic
(Oct 13, 2020)
criteria provided, single submitter
Method: clinical testing
Glycogen storage disease, type II
Allele origin: germline
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001442688.1
Submitted: (Nov 10, 2020)
Evidence details
Publications
PubMed (4)
Comment:
Variant summary: GAA c.2297A>G (p.Tyr766Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Pathogenic
(Oct 16, 2020)
criteria provided, single submitter
Method: clinical testing
Glycogen storage disease, type II
Allele origin: germline
Invitae
Accession: SCV001213921.2
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (4)
Comment:
This sequence change replaces tyrosine with cysteine at codon 766 of the GAA protein (p.Tyr766Cys). The tyrosine residue is highly conserved and there is a … (more)
Likely pathogenic
(Jun 30, 2021)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV001796063.1
Submitted: (Aug 19, 2021)
Evidence details
Comment:
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Reported in ClinVar but additional evidence is not available (ClinVar Variant … (more)
Likely pathogenic
(Jul 22, 2021)
criteria provided, single submitter
Method: clinical testing
Glycogen storage disease, type II
Allele origin: germline
Nilou-Genome Lab
Accession: SCV001810186.1
Submitted: (Aug 30, 2021)
Evidence details
Likely pathogenic
(Jan 22, 2020)
no assertion criteria provided
Method: curation
Glycogen storage disease, type II
(Autosomal recessive inheritance)
Allele origin: germline
Broad Institute Rare Disease Group, Broad Institute
Accession: SCV001422964.1
Submitted: (Mar 09, 2020)
Evidence details
Publications
PubMed (3)
Other databases
https://erepo.clinicalgenome.org…
Comment:
The p.Tyr766Cys variant in GAA has been reported in at least two individuals with glycogen storage disease II (PMID: 22676651, 21605996, 29124014) and has been … (more)
Likely pathogenic
(Aug 07, 2019)
no assertion criteria provided
Method: clinical testing
not provided
Allele origin: germline
PerkinElmer Genomics
Accession: SCV002025201.1
Submitted: (Nov 19, 2021)
Evidence details

Functional evidence

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There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Citations for this variant

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Title Author Journal Year Link
Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients. Nallamilli BRR Annals of clinical and translational neurology 2018 PMID: 30564623
A molecular analysis of the GAA gene and clinical spectrum in 38 patients with Pompe disease in Japan. Fukuhara Y Molecular genetics and metabolism reports 2017 PMID: 29124014
Clinical and Molecular Characterization of Infantile-Onset Pompe Disease in Mainland Chinese Patients: Identification of Two Common Mutations. Chen X Genetic testing and molecular biomarkers 2017 PMID: 28394184
A cross-sectional single-centre study on the spectrum of Pompe disease, German patients: molecular analysis of the GAA gene, manifestation and genotype-phenotype correlations. Herzog A Orphanet journal of rare diseases 2012 PMID: 22676651
The emerging phenotype of long-term survivors with infantile Pompe disease. Prater SN Genetics in medicine : official journal of the American College of Medical Genetics 2012 PMID: 22538254
Expanding the clinical spectrum of late-onset Pompe disease: dilated arteriopathy involving the thoracic aorta, a novel vascular phenotype uncovered. El-Gharbawy AH Molecular genetics and metabolism 2011 PMID: 21605996
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GAA - - - -
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/6db8818b-e483-4da7-b280-e13cbacb002b - - - -

Text-mined citations for rs144016984...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 28, 2021