ClinVar Genomic variation as it relates to human health
NM_000152.5(GAA):c.1375G>A (p.Asp459Asn)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000152.5(GAA):c.1375G>A (p.Asp459Asn)
Variation ID: 188480 Accession: VCV000188480.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q25.3 17: 80109993 (GRCh38) [ NCBI UCSC ] 17: 78083792 (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 Jul 2, 2017 Jun 17, 2024 Mar 5, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000152.5:c.1375G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000143.2:p.Asp459Asn missense NM_000152.4:c.1375G>A NM_001079803.3:c.1375G>A NP_001073271.1:p.Asp459Asn missense NM_001079804.3:c.1375G>A NP_001073272.1:p.Asp459Asn missense NC_000017.11:g.80109993G>A NC_000017.10:g.78083792G>A NG_009822.1:g.13438G>A LRG_673:g.13438G>A LRG_673t1:c.1375G>A - Protein change
- D459N
- Other names
- NM_000152.5(GAA):c.1375G>A
- Canonical SPDI
- NC_000017.11:80109992:G:A
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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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0.00020 (A)
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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00003
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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 |
2798 | 2850 |
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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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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May 10, 2023 | RCV000493868.9 | |
Uncertain significance (7) |
reviewed by expert panel
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Mar 5, 2024 | RCV000631097.17 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 30, 2022 | RCV002469040.1 |
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
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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
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. |
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Uncertain significance
(Mar 05, 2024)
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reviewed by expert panel
Method: curation
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Glycogen storage disease, type II
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV004809074.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
Comment:
The NM_000152.5:c.1375G>A variant in GAA is a missense variant predicted to cause substitution of Asp by Asn at amino acid 459 (p.Asp459Asn). The highest population … (more)
The NM_000152.5:c.1375G>A variant in GAA is a missense variant predicted to cause substitution of Asp by Asn at amino acid 459 (p.Asp459Asn). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00041 (14/34538 alleles) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). At least 4 patients have been identified with this variant. Two had documented GAA deficiency, one with <30% of normal mean control level of GAA activity in skin fibroblasts (PMID: 21757382; 18458862) and one within affected range in dried blood spot (Clinical diagnostic laboratory). (PP4_Moderate). Of these patients, one was compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, and confirmed to be in trans, c.2173C>T (p.Arg725Trp) (ClinVar Variation ID: 4024, SCV004227911.1). 1 point (PM3). Additional patients had evidence of pseudodeficiency variants with (PMID: 21484825, 28302345). The computational predictor REVEL gives a score of 0.531 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. There is a ClinVar entry for this variant (Variation ID: 188480). In summary, this variant meets the criteria to be classified as Uncertain significance for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 2.0): PM2_supporting, PP4_Moderate, PM3. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on March 5, 2024). (less)
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Uncertain significance
(Nov 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002765934.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Variant summary: GAA c.1375G>A (p.Asp459Asn) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging … (more)
Variant summary: GAA c.1375G>A (p.Asp459Asn) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 250268 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (7.2e-05 vs 0.0042), allowing no conclusion about variant significance. c.1375G>A has been reported in the literature in multiple individuals affected with late onset Glycogen Storage Disease, Type 2 (Pompe Disease) (examples: Wan_2008, Bali_2011, Yang_GAA_2011 and Sawada_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=1) and VUS (n=6). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
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Uncertain significance
(May 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003828485.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Uncertain significance
(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: SCV001422900.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022 |
Comment:
The heterozygous p.Asp459Asn variant in GAA has been reported in 3 individuals (including 1 individual from China and 1 individual from Taiwan individual) with Glycogen … (more)
The heterozygous p.Asp459Asn variant in GAA has been reported in 3 individuals (including 1 individual from China and 1 individual from Taiwan individual) with Glycogen Storage Disease II (PMID: 18458862, 21484825, 21757382), and has been reported as a VUS by EGL, Invitae, GeneDx, and Counsyl in ClinVar (Variation ID: 188480). This variant has been identified in 0.041% (14/34538) of Latino chromosomes, 0.005% (1/18370) of East Asian chromosomes, and 0.003% (3/112916) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs535644999). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. Additional computational prediction tools suggest the variant affects protein structure and stability (PMID: 29061980). However, the Aspartate (Asp) at position 459 is highly conserved in mammals and evolutionary distant species and one additional variant at the same position (p.Asp459His) has been reported as a VUS in ClinVar (Variation ID: 497673), raising the possibility that a change at this position may not be tolerated. The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in assays of relevant tissue (PMID: 18458862, 21757382). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP4 (Richards 2015). (less)
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Pathogenic
(Mar 02, 2024)
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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: SCV004195440.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Uncertain significance
(Oct 08, 2018)
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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: SCV000582900.4
First in ClinVar: Jul 02, 2017 Last updated: Apr 17, 2019 |
Comment:
A variant of uncertain significance has been identified in the GAA gene. The D459N variant in the GAA gene has previously been reported in association … (more)
A variant of uncertain significance has been identified in the GAA gene. The D459N variant in the GAA gene has previously been reported in association with late-onset Pompe disease in individuals who harbored a second missense variant in GAA, although the phase of these variants was not determined in these individuals (Wan et al., 2008; Yang et al., 2011, Bali et al., 2011). This variant is observed in 16/245730 (0.0065%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). Nevertheless, the D459N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. (less)
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Uncertain significance
(Sep 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disease, type II
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002027268.1
First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021 |
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Pathogenic
(Dec 28, 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: SCV000752090.5
First in ClinVar: May 28, 2018 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 459 of the GAA protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 459 of the GAA protein (p.Asp459Asn). This variant is present in population databases (rs535644999, gnomAD 0.04%). This missense change has been observed in individual(s) with Pompe disease (PMID: 18458862, 21484825, 21757382). ClinVar contains an entry for this variant (Variation ID: 188480). 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%. For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain significance
(Feb 20, 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: SCV000798024.1
First in ClinVar: May 28, 2018 Last updated: May 28, 2018 |
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Uncertain significance
(Oct 06, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000702471.2
First in ClinVar: Jan 26, 2017 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Uncertain significance
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Glycogen storage disease type II
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001455612.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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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Newborn Screening for Pompe Disease. | Sawada T | International journal of neonatal screening | 2020 | PMID: 33073027 |
Structure of human lysosomal acid α-glucosidase-a guide for the treatment of Pompe disease. | Roig-Zamboni V | Nature communications | 2017 | PMID: 29061980 |
Rapid progressive course of later-onset Pompe disease in Chinese patients. | Yang CC | Molecular genetics and metabolism | 2011 | PMID: 21757382 |
Molecular analysis and protein processing in late-onset Pompe disease patients with low levels of acid α-glucosidase activity. | Bali DS | Muscle & nerve | 2011 | PMID: 21484825 |
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 | Journal of neurology | 2008 | PMID: 18458862 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GAA | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/a13f5909-eb8f-4d45-a198-4758c4612e8e | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/f71025a1-9f3e-4f44-82a5-ae2e28f9a314 | - | - | - | - |
Text-mined citations for rs535644999 ...
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.