ClinVar Genomic variation as it relates to human health
NM_000152.5(GAA):c.1856G>A (p.Ser619Asn)
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.1856G>A (p.Ser619Asn)
Variation ID: 370146 Accession: VCV000370146.52
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q25.3 17: 80112679 (GRCh38) [ NCBI UCSC ] 17: 78086478 (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 Jan 7, 2017 Apr 20, 2024 Jan 20, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000152.5:c.1856G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000143.2:p.Ser619Asn missense NM_001079803.3:c.1856G>A NP_001073271.1:p.Ser619Asn missense NM_001079804.3:c.1856G>A NP_001073272.1:p.Ser619Asn missense NC_000017.11:g.80112679G>A NC_000017.10:g.78086478G>A NG_009822.1:g.16124G>A LRG_673:g.16124G>A LRG_673t1:c.1856G>A - Protein change
- S619N
- Other names
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- Canonical SPDI
- NC_000017.11:80112678: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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Allele frequency
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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) 0.00004
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 |
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
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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 (8) |
criteria provided, multiple submitters, no conflicts
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Jan 20, 2024 | RCV000409055.17 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 16, 2023 | RCV001726152.18 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 10, 2021 | RCV001814152.2 |
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. |
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Pathogenic
(Jan 10, 2019)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001361531.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: GAA c.1856G>A (p.Ser619Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: GAA c.1856G>A (p.Ser619Asn) results in a conservative amino acid change in 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 1.7e-05 in 237486 control chromosomes (gnomAD). The variant, c.1856G>A, has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease)(Kroos_2006, Remiche_2014, Gallardo_2011, Parenti_2014, Arslan_2016). One patient, Arslan_2016, was found to be homozygous for two deleterious variants, the variant of interest and c.32-13T>G, to which the authors indicate the phenotype was more progressive. The patient was born to consanguineous Turkish parents. These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of residual acid -glucosidase activity (Kroos_2006). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Jul 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Abnormality of metabolism/homeostasis
Affected status: unknown
Allele origin:
germline
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Kariminejad - Najmabadi Pathology & Genetics Center
Accession: SCV001755320.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
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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: SCV001422906.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 02, 2022 |
Comment:
The p.Ser619Asn variant in GAA has been reported in 8 individuals with Glycogen Storage Disease II (PMID: 22194990, 26946079, 22980766, 16838077, 24158270, 25052852, 23668440, 25998610). … (more)
The p.Ser619Asn variant in GAA has been reported in 8 individuals with Glycogen Storage Disease II (PMID: 22194990, 26946079, 22980766, 16838077, 24158270, 25052852, 23668440, 25998610). This variant has also been reported likely pathogenic by Counsyl in ClinVar (Variation ID: 370146) and has been identified in 0.013% (4/29974) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs753269119). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the p.Ser619Asn variant may impact proteolytic activation of GAA and GAA activity (PMID: 16838077, 19862843). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One pathogenic additional variant at the the same position, p.Ser619Arg, has been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 550825). The presence of this variant in combination with a pathogenic variant and in an individual with Glycogen Storage Disease II increases the likelihood that the p.Ser619Asn variant is pathogenic (PMID: 16838077). Of note, this variant has also been observed in cis with the known pathogenic variant c.-32-13T>G with both variants in the homozygous state in an individual with Glycogen Storage Disorder II (PMID: 26946079). The phenotype of individuals homozygous and heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in relevant tissue, consistent with disease (PMID: 24158270, 26946079, 16838077). 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, another pathogenic variant at the same position, and low frequency in the general population. ACMG/AMP Criteria applied: PS3, PM2, PM5, PP3, PM3_Supporting, PP4 (Richards 2015). (less)
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Likely pathogenic
(Nov 30, 2015)
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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: SCV000485388.2
First in ClinVar: Jan 07, 2017 Last updated: Dec 24, 2022 |
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Pathogenic
(Feb 17, 2022)
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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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Fulgent Genetics, Fulgent Genetics
Accession: SCV002780847.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jul 06, 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: SCV004197802.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Aug 16, 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: SCV002025204.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 20, 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:
germline
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Invitae
Accession: SCV001409389.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 619 of the GAA protein (p.Ser619Asn). … (more)
This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 619 of the GAA protein (p.Ser619Asn). This variant is present in population databases (rs753269119, gnomAD 0.01%). This missense change has been observed in individual(s) with Pompe disease (PMID: 16838077, 22990675, 24158270, 25998610, 26946079). ClinVar contains an entry for this variant (Variation ID: 370146). 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: 19862843). This variant disrupts the p.Ser619 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14643388, 21471980, 25213570, 27363342, 29124014). 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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Pathogenic
(Sep 01, 2021)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001961733.14
First in ClinVar: Oct 08, 2021 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Nov 03, 2022)
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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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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848817.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Ser619Asn variant in GAA has been reported in at least 8 individuals (6 in the compound heterozygous state) with Glycogen Storage Disease II. Of … (more)
The p.Ser619Asn variant in GAA has been reported in at least 8 individuals (6 in the compound heterozygous state) with Glycogen Storage Disease II. Of note, in 2 of these individuals (one homozygote and one compound heterozygote), this variant was in cis with the known pathogenic variant c.-32-13T>G (Gallardo 2011 PMID: 22194990, Arslan 2016 PMID: 26946079, Alejaldre 2012 PMID: 22980766, Kroos 2006 PMID: 16838077, Remiche 2014 PMID: 24158270, Parenti 2014 PMID: 25052852, Fecarotta 2013 PMID: 23668440, Gutiérrez-Rivas 2015 PMID: 25998610). This variant has also been reported in ClinVar (Variation ID: 370146) and has been identified in 2/4830 of South Asian and 1/67968 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies using patient tissues provide some evidence that this variant may impact proteolytic activation of GAA and GAA activity (Kroos 2006 PMID: 16838077). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Another variant involving this codon (p.Ser619Arg) has been identified in individuals with autosomal recessive Glycogen Storage Disease II and is classified as likely pathogenic/pathogenic in ClinVar. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Glycogen Storage Disease II. ACMG/AMP Criteria applied: PS3_Moderate, PM2_Supporting, PM5, PP3, PM3_Very strong. (less)
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Pathogenic
(Apr 10, 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: SCV002092071.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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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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 |
Discovery of pathogenic variants in a large Korean cohort of inherited muscular disorders. | Park HJ | Clinical genetics | 2017 | PMID: 27363342 |
Combination of two different homozygote mutations in Pompe disease. | Arslan A | Pediatrics international : official journal of the Japan Pediatric Society | 2016 | PMID: 26946079 |
Targeted screening for the detection of Pompe disease in patients with unclassified limb-girdle muscular dystrophy or asymptomatic hyperCKemia using dried blood: A Spanish cohort. | Gutiérrez-Rivas E | Neuromuscular disorders : NMD | 2015 | PMID: 25998610 |
Hypertrophic cardiomyopathy in pompe disease is not limited to the classic infantile-onset phenotype. | Lee DH | JIMD reports | 2014 | PMID: 25213570 |
A chaperone enhances blood α-glucosidase activity in Pompe disease patients treated with enzyme replacement therapy. | Parenti G | Molecular therapy : the journal of the American Society of Gene Therapy | 2014 | PMID: 25052852 |
Extended phenotype description and new molecular findings in late onset glycogen storage disease type II: a northern Italy population study and review of the literature. | Remiche G | Journal of neurology | 2014 | PMID: 24158270 |
Improvement of dysphagia in a child affected by Pompe disease treated with enzyme replacement therapy. | Fecarotta S | Italian journal of pediatrics | 2013 | PMID: 23668440 |
Pharmacological enhancement of α-glucosidase by the allosteric chaperone N-acetylcysteine. | Porto C | Molecular therapy : the journal of the American Society of Gene Therapy | 2012 | PMID: 22990675 |
Trunk muscle involvement in late-onset Pompe disease: study of thirty patients. | Alejaldre A | Neuromuscular disorders : NMD | 2012 | PMID: 22980766 |
Comparison of dysferlin expression in human skeletal muscle with that in monocytes for the diagnosis of dysferlin myopathy. | Gallardo E | PloS one | 2011 | PMID: 22194990 |
Biochemical and structural study on a S529V mutant acid α-glucosidase responsive to pharmacological chaperones. | Tajima Y | Journal of human genetics | 2011 | PMID: 21471980 |
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 |
Seven cases of Pompe disease from Greece. | Kroos M | Journal of inherited metabolic disease | 2006 | PMID: 16838077 |
New GAA mutations in Japanese patients with GSDII (Pompe disease). | Pipo JR | Pediatric neurology | 2003 | PMID: 14643388 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/174a1ab6-5a39-418c-9745-dbb14fbceb13 | - | - | - | - |
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Text-mined citations for rs753269119 ...
HelpRecord last updated Apr 20, 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.