ClinVar Genomic variation as it relates to human health
NM_000152.5(GAA):c.670C>T (p.Arg224Trp)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000152.5(GAA):c.670C>T (p.Arg224Trp)
Variation ID: 189188 Accession: VCV000189188.28
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17q25.3 17: 80105872 (GRCh38) [ NCBI UCSC ] 17: 78079671 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 29, 2015 Feb 14, 2024 May 3, 2020 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000152.5:c.670C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000143.2:p.Arg224Trp missense NM_001079803.3:c.670C>T NP_001073271.1:p.Arg224Trp missense NM_001079804.3:c.670C>T NP_001073272.1:p.Arg224Trp missense NC_000017.11:g.80105872C>T NC_000017.10:g.78079671C>T NG_009822.1:g.9317C>T LRG_673:g.9317C>T LRG_673t1:c.670C>T P10253:p.Arg224Trp - Protein change
- R224W
- Other names
- -
- Canonical SPDI
- NC_000017.11:80105871:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
GAA | - | - |
GRCh38 GRCh38 GRCh37 |
2757 | 2807 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Pathogenic (10) |
reviewed by expert panel
|
May 3, 2020 | RCV000169620.23 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Oct 26, 2023 | RCV000272542.11 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
---|---|---|---|---|---|
Pathogenic
(May 03, 2020)
|
reviewed by expert panel
Method: curation
|
Glycogen storage disease, type II
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel
Accession: SCV001371775.1
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
This variant, c.670C>T (p.Arg224Trp) has been reported in at least 6 individuals with Pompe disease and deficient GAA activity meeting the ClinGen LSD VCEP's PP4 … (more)
This variant, c.670C>T (p.Arg224Trp) has been reported in at least 6 individuals with Pompe disease and deficient GAA activity meeting the ClinGen LSD VCEP's PP4 specifications. All of these individuals are compound heterozygous for the variant and a unique pathogenic variant, including c.-32-13T>G (PMID 25673129; phase unknown), c.525delT (PMID 12923862; phase unknown), c.763C > T (p.Gln255Ter) (PMID 25026126, confirmed in trans), c.2237G>A (p.Trp746Ter) (PMID 12923862; phase unknown), c.1064T>C (p.Leu355Pro)(PMID 23632174; confirmed in trans), and c.1979G>A (p.Arg660His) (PMID 14643388; phase unknown). These data meet PM3_Strong. Note that the in trans data from the patients with c.1064T>C (p.Leu355Pro) and c.1979G>A (p.Arg660His) will be used in the assessment of those variants and was not used here in order to avoid a circular argument. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 in the European non-Finnish population, meeting PM2. The score for the in silico meta-predictor REVEL, does not meet PP3 or BP4. However, when expressed in COS cells, this variant results in significantly reduced GAA activity, <10% of wild type (PMID 12923862, 14643388, 19862843), meeting PS3. There is a ClinVar entry for this variant (Variation ID: 189188, 1 star review status), with two submitters classifying the variant as pathogenic, one as likely pathogenic, and one as a variant of uncertain significance. In summary, the variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PS3, PM2, PM3_Strong, PP4. (less)
|
|
Uncertain significance
(Nov 07, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000339005.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Number of individuals with the variant: 2
Sex: mixed
|
|
Pathogenic
(Jun 04, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease, type II
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919382.1
First in ClinVar: Jun 03, 2019 Last updated: Jun 03, 2019 |
Comment:
Variant summary: GAA c.670C>T (p.Arg224Trp) results in a non-conservative amino acid change located in the Galactose mutarotase, N-terminal barrel of the encoded protein sequence. Four … (more)
Variant summary: GAA c.670C>T (p.Arg224Trp) results in a non-conservative amino acid change located in the Galactose mutarotase, N-terminal barrel of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.2e-05 in 269992 control chromosomes (gnomAD and publications). The variant, c.670C>T, has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (Angelini_2012, Habbal_2013, Pipo_2003, Pittis_2003, Pittis_2008). These data indicate that the variant is likely to be associated with disease. Multiple publications have functionally assessed the variant indicating the variant significantly impedes GAA enzymatic activity (Angelini_2012, Pipo_2003, Pittis_2003). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely pathogenic or uncertain significance without additional evidence to independently evaluate. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Pathogenic
(Jan 22, 2020)
|
criteria provided, single submitter
Method: curation
|
Glycogen storage disease, type II
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001422667.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022 |
Comment:
The heterozygous p.Arg224Trp variant in GAA has been reported in the compound heterozygous state in 6 individuals with Glycogen Storage Disease II (PMID: 25673129, 12923862, … (more)
The heterozygous p.Arg224Trp variant in GAA has been reported in the compound heterozygous state in 6 individuals with Glycogen Storage Disease II (PMID: 25673129, 12923862, 25026126, 23632174, 14643388), and has been identified 0.005% (6/127580) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs757700700). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported as a VUS by EGL Genetic Diagnostics, a likely pathogenic variant by Counsyl, and a pathogenic variant by Invitae and Integrated Genetics in ClinVar (Variation ID: 189188). In vitro functional studies provide some evidence that the p.Arg224Trp variant may impact GAA activity (PMID: 19862843, 14643388, 12923862). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The presence of this variant in combination with pathogenic variants and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Arg224Trp variant is pathogenic (PMID: 12923862, 25673129, 25026126). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on in vitro functional studies and multiple occurrences with pathogenic variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PM3_Strong, PS3, PM2, PP4 (Richards 2015). (less)
|
|
Pathogenic
(Jan 13, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease, type II
Affected status: unknown
Allele origin:
unknown
|
Illumina Laboratory Services, Illumina
Accession: SCV002540234.1
First in ClinVar: Jul 06, 2022 Last updated: Jul 06, 2022 |
Comment:
The GAA c.670C>T (p.Arg224Trp) missense variant results in the substitution of arginine at amino acid position 224 with tryptophan. Across a selection of the available … (more)
The GAA c.670C>T (p.Arg224Trp) missense variant results in the substitution of arginine at amino acid position 224 with tryptophan. Across a selection of the available literature, the c.670C>T variant has been identified in a compound heterozygous state in at least six individuals affected with glycogen storage disease, type II (Pipo et al. 2003; Pittis et al. 2003; Zouheir Habbal et al. 2013; Aykut et al. 2014; Parini et al. 2018). Affected individuals show reduced alpha-glucosidase activity and onset of the disease is influenced by the second pathogenic variant found in trans. The c.670C>T variant is reported in the Genome Aggregation Database in six alleles at a frequency of 0.000047 in the European (non-Finnish) population (version 2.1.1). Functional studies demonstrated that when the c.670C>T variant protein was expressed in cells, glucosidase enzyme activity was reduced to 2-10% of wild-type activity (Pittis et al. 2003; Pipo et al. 2003; Flanagan et al. 2009). Based on the available evidence, the c.670C>T (p.Arg224Trp) variant is classified as pathogenic for glycogen storage disease, type II. (less)
|
|
Likely pathogenic
(Feb 19, 2015)
|
criteria provided, single submitter
Method: literature only
|
Glycogen storage disease, type II
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000221147.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
|
|
Pathogenic
(Nov 21, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease, type II
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002780880.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
Pathogenic
(Oct 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease, type II
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004195431.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
Pathogenic
(Oct 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002021167.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Oct 29, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502282.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 2
Secondary finding: no
|
|
Pathogenic
(Nov 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease, type II
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000831593.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 224 of the GAA protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 224 of the GAA protein (p.Arg224Trp). This variant is present in population databases (rs757700700, gnomAD 0.004%). This missense change has been observed in individuals with Pompe disease (PMID: 12923862, 14643388, 18429042, 25026126, 29422078). ClinVar contains an entry for this variant (Variation ID: 189188). 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%. Experimental studies have shown that this missense change affects GAA function (PMID: 12923862, 14643388, 19862843). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Glycogen storage disease type II
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001453594.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
Glycogen storage disease, type II
Affected status: unknown
Allele origin:
germline
|
GenomeConnect, ClinGen
Accession: SCV001338892.1
First in ClinVar: Jun 19, 2020 Last updated: Jun 19, 2020 |
Comment:
Variant interpretted as Pathogenic and reported on 04-29-2019 by Lab or GTR ID 500068. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpretted as Pathogenic and reported on 04-29-2019 by Lab or GTR ID 500068. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Myopia (disease) (present) , Anxiety (present) , Depressivity (present) , Asthma (present)
Indication for testing: Family Testing
Age: 20-29 years
Sex: female
Testing laboratory: Mayo Clinic Laboratories,Mayo Clinic
Date variant was reported to submitter: 2019-04-29
Testing laboratory interpretation: Pathogenic
|
|
click to load more click to collapse |
Germline Functional Evidence
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 germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Update of the Pompe variant database for the prediction of clinical phenotypes: Novel disease-associated variants, common sequence variants, and results from newborn screening. | de Faria DOS | Human mutation | 2021 | PMID: 33560568 |
Clinical characteristics and genotypes in the ADVANCE baseline data set, a comprehensive cohort of US children and adolescents with Pompe disease. | Kishnani PS | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 31086307 |
Pilot study of expanded carrier screening for 11 recessive diseases in China: results from 10,476 ethnically diverse couples. | Zhao S | European journal of human genetics : EJHG | 2019 | PMID: 30275481 |
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 |
Long term clinical history of an Italian cohort of infantile onset Pompe disease treated with enzyme replacement therapy. | Parini R | Orphanet journal of rare diseases | 2018 | PMID: 29422078 |
Clinical and molecular aspects of 30 patients with late-onset Pompe disease (LOPD): unusual features and response to treatment. | Montagnese F | Journal of neurology | 2015 | PMID: 25673129 |
Two novel mutations in acid α-glucosidase gene in two patients with Pompe disease. | Aykut A | Journal of pediatric endocrinology & metabolism : JPEM | 2014 | PMID: 25026126 |
Alkaptonuria and Pompe disease in one patient: metabolic and molecular analysis. | Zouheir Habbal M | BMJ case reports | 2013 | PMID: 23632174 |
Observational clinical study in juvenile-adult glycogenosis type 2 patients undergoing enzyme replacement therapy for up to 4 years. | Angelini C | Journal of neurology | 2012 | PMID: 22081099 |
The pharmacological chaperone 1-deoxynojirimycin increases the activity and lysosomal trafficking of multiple mutant forms of acid alpha-glucosidase. | Flanagan JJ | Human mutation | 2009 | PMID: 19862843 |
Molecular and functional characterization of eight novel GAA mutations in Italian infants with Pompe disease. | Pittis MG | Human mutation | 2008 | PMID: 18429042 |
New GAA mutations in Japanese patients with GSDII (Pompe disease). | Pipo JR | Pediatric neurology | 2003 | PMID: 14643388 |
Identification of four novel mutations in the alpha glucosidase gene in five Italian patients with infantile onset glycogen storage disease type II. | Pittis MG | American journal of medical genetics. Part A | 2003 | PMID: 12923862 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GAA | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/1f6327c8-2794-45a5-a3b1-4998dee695e7 | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/ae3e1504-d068-414a-ac8e-b270e5fa1d23 | - | - | - | - |
click to load more click to collapse |
Text-mined citations for rs757700700 ...
HelpRecord last updated Mar 30, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.