ClinVar Genomic variation as it relates to human health
NM_000152.5(GAA):c.1933G>T (p.Asp645Tyr)
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
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NM_000152.5(GAA):c.1933G>T (p.Asp645Tyr)
Variation ID: 556386 Accession: VCV000556386.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q25.3 17: 80112920 (GRCh38) [ NCBI UCSC ] 17: 78086719 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Aug 5, 2018 Sep 29, 2024 Mar 14, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000152.5:c.1933G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000143.2:p.Asp645Tyr missense NM_000152.4:c.1933G>T NM_001079803.3:c.1933G>T NP_001073271.1:p.Asp645Tyr missense NM_001079804.3:c.1933G>T NP_001073272.1:p.Asp645Tyr missense NC_000017.11:g.80112920G>T NC_000017.10:g.78086719G>T NG_009822.1:g.16365G>T LRG_673:g.16365G>T LRG_673t1:c.1933G>T - Protein change
- D645Y
- Other names
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- Canonical SPDI
- NC_000017.11:80112919:G:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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GAA | - | - |
GRCh38 GRCh38 GRCh37 |
2801 | 2853 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Dec 2, 2023 | RCV000672387.12 | |
GAA-related disorder
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Likely pathogenic (1) |
criteria provided, single submitter
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Dec 21, 2022 | RCV003411583.5 |
Pathogenic (1) |
criteria provided, single submitter
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Mar 14, 2024 | RCV004719935.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
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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
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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
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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. |
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Pathogenic
(Jan 22, 2020)
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criteria provided, single submitter
Method: curation
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Glycogen storage disease, type II
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001422989.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 02, 2022 |
Comment:
The p.Asp645Tyr variant in GAA has been reported in four individuals with glycogen storage disease II, segregated with disease in 2 affected relatives from 1 … (more)
The p.Asp645Tyr variant in GAA has been reported in four individuals with glycogen storage disease II, segregated with disease in 2 affected relatives from 1 family (PMID: 18425781, 17616415; DOI: 10.1016/j.jns.2015.08.1211) and has been identified in 0.007% (1/15154) of African chromosomes and 0.003% (1/33952) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs368438393). 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 in ClinVar as likely pathogenic by Counsyl (VariationID: 556386). In vitro studies using cells transfected with the variant provide some evidence that the p.Asp645Tyr variant may impact protein function (PMID: 18425781). However, these types of assays may not accurately represent biological function. Three additional pathogenic variants, resulting in a different amino acid change at the same position (p.Asp645Asn, p.Asp645His, and p.Asp645Glu) have been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (VariationID: 188728, 189013, 4029). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of an individual heterozygous for this variant is highly specific for glycogen storage disease II based on GAA enzyme activity in fibroblasts being <20% of wild type, consistent with disease (PMID: 17616415). Additionally, the presence of this variant in combination with reported pathogenic variant c.-32-13T>G (VariationID: 4027; PMID: 17616415, https://doi.org/10.1016/j.jns.2015.08.1211) and in individuals with glycogen storage disease II silghtly increases the likelihood that the p.Asp645Tyr variant is pathogenic. In summary, this variant meets criteria to be classified as pathogenic for glycogen storage disease II in an autosomal recessive manner based on functional studies demonstrating a potential impact on the protein, previous reports of other pathogenic variants at the same location, and the presence of the variant in combination with a pathogenic variant in an affected individual. ACMG/AMP Criteria applied: PM5_Strong, PS3, PM2, PM3_Supporting, PP3, PP4 (Richards 2015). (less)
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Pathogenic
(Oct 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type II
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002212531.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 645 of the GAA protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 645 of the GAA protein (p.Asp645Tyr). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with Pompe disease (PMID: 17616415, 24715333). ClinVar contains an entry for this variant (Variation ID: 556386). 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. This variant disrupts the p.Asp645 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10338092, 21039225, 21232767, 21439876, 21757382, 24269976). 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. (less)
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Likely pathogenic
(Dec 21, 2022)
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criteria provided, single submitter
Method: clinical testing
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GAA-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004111356.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The GAA c.1933G>T variant is predicted to result in the amino acid substitution p.Asp645Tyr. This variant, along with a second pathogenic GAA variant, has been … (more)
The GAA c.1933G>T variant is predicted to result in the amino acid substitution p.Asp645Tyr. This variant, along with a second pathogenic GAA variant, has been reported in multiple individuals with glycogen storage disease 2 (Gort et al. 2007. PubMed ID: 17616415; van Gelder et al. 2015. PMID: 24715333; Figueroa-Bonaparte et al. 2016 PMID: 27711114; Ebbink et al. 2018. PMID:29573408; Amiñoso et al. 2022. PubMed ID: 34530085). In the fibroblasts of an individual that was also heterozygous for the c.-32-13T>G variant had residual GAA activity of ~20% (Gort et al. 2007. PubMed ID: 17616415). This variant is reported in 0.0066% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-78086719-G-T). This variant is interpreted as likely pathogenic. (less)
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Pathogenic
(Mar 14, 2024)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV005325576.1
First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024 |
Comment:
Published functional studies found this variant is associated with no detectable enzyme activity (PMID: 18425781); Not observed at significant frequency in large population cohorts (gnomAD); … (more)
Published functional studies found this variant is associated with no detectable enzyme activity (PMID: 18425781); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30281819, 26944269, 35787971, 31342611, 30049495, 22253258, 19343043, 24715333, 17616415, 29573408, 18425781, 34530085) (less)
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Pathogenic
(Dec 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type II
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004195467.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Likely pathogenic
(Jan 28, 2018)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type II
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000797486.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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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 |
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Enzyme therapy and immune response in relation to CRIM status: the Dutch experience in classic infantile Pompe disease. | van Gelder CM | Journal of inherited metabolic disease | 2015 | PMID: 24715333 |
Clinical and molecular genetic study of infantile-onset Pompe disease in Chinese patients: identification of 6 novel mutations. | Fu L | Gene | 2014 | PMID: 24269976 |
Rapid progressive course of later-onset Pompe disease in Chinese patients. | Yang CC | Molecular genetics and metabolism | 2011 | PMID: 21757382 |
Pompe disease: design, methodology, and early findings from the Pompe Registry. | Byrne BJ | Molecular genetics and metabolism | 2011 | PMID: 21439876 |
Later-onset Pompe disease: early detection and early treatment initiation enabled by newborn screening. | Chien YH | The Journal of pediatrics | 2011 | PMID: 21232767 |
p.D645E of acid α-glucosidase is the most common mutation in thai patients with infantile-onset pompe disease. | Amarinthnukrowh P | Genetic testing and molecular biomarkers | 2010 | PMID: 21039225 |
Update of the Pompe disease mutation database with 107 sequence variants and a format for severity rating. | Kroos M | Human mutation | 2008 | PMID: 18425781 |
Glycogen storage disease type II in Spanish patients: high frequency of c.1076-1G>C mutation. | Gort L | Molecular genetics and metabolism | 2007 | PMID: 17616415 |
Molecular genetic study of Pompe disease in Chinese patients in Taiwan. | Ko TM | Human mutation | 1999 | PMID: 10338092 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/74e0fdef-dabd-4903-9420-23593889374f | - | - | - | - |
Text-mined citations for rs368438393 ...
HelpRecord last updated Oct 08, 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.