ClinVar Genomic variation as it relates to human health
NM_000152.5(GAA):c.1437G>A (p.Lys479=)
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.1437G>A (p.Lys479=)
Variation ID: 188044 Accession: VCV000188044.3
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q25.3 17: 80110055 (GRCh38) [ NCBI UCSC ] 17: 78083854 (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 27, 2015 Feb 2, 2022 Jan 22, 2020 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000152.5:c.1437G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000143.2:p.Lys479= synonymous NM_001079803.3:c.1437G>A NP_001073271.1:p.Lys479= synonymous NM_001079804.3:c.1437G>A NP_001073272.1:p.Lys479= synonymous NC_000017.11:g.80110055G>A NC_000017.10:g.78083854G>A NG_009822.1:g.13500G>A LRG_673:g.13500G>A LRG_673t1:c.1437G>A - Protein change
- Other names
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- Canonical SPDI
- NC_000017.11:80110054: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), exomes 0.00000
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
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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
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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Likely pathogenic (2) |
criteria provided, single submitter
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Jan 22, 2020 | RCV000186551.4 |
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
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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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Likely 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: SCV001422885.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 02, 2022 |
Comment:
The c.1437G>A (p.Lys479=) variant in GAA has been reported in 4 individuals (including 1 from the UK, 1 Guatemalan, and 1 Arabic individuals) with Glycogen … (more)
The c.1437G>A (p.Lys479=) variant in GAA has been reported in 4 individuals (including 1 from the UK, 1 Guatemalan, and 1 Arabic individuals) with Glycogen Storage Disease II (PMID: 26873529, 18425781, 25243733, 26160551), and has also been reported pathogenic by the Freeman-Sheldon Research Group (deGruyter-McKusick Institute of Health Sciences) in ClinVar based on a case family (Variation ID: 188044). This variant has been identified in 0.003% (1/30606) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs796051877). 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 c.1437G>A variant may impact GAA expression and splicing (PMID: 18425781, 25243733). However, these types of assays may not accurately represent biological function. This variant is located in the last three bases of the exon, which is part of the 5' splice region. Computational prediction tools and conservation analyses suggest that this variant may impact splicing, though this information is not predictive enough to determine pathogenicity. The presence of this variant in the homozygous state and in an individual with Glycogen Storage Disease II increases the likelihood that the c.1437G>A variant is pathogenic (PMID: 25243733). The phenotype of an individual homozygous for this variant is highly specific for Glycogen Storage Disease II based on abnormally low GAA activity detected in their fibroblasts (PMID: 25243733). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM3_Supporting, PP3, PP4, PM2, PS3_Supporting (Richards 2015). (less)
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Pathogenic
(Dec 21, 2014)
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no assertion criteria provided
(clinical testing)
Method: clinical testing
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Glycogen storage disease, type II
Affected status: yes
Allele origin:
germline
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Freeman-Sheldon Research Group, deGruyter-McKusick Institute of Health Sciences
Additional submitters:
Paediatrics, Hospital General San Juan de Dios
Clinical Molecular Diagnostics Laboratory, Duke University Health System
Accession: SCV000211952.1
First in ClinVar: Jul 27, 2015 Last updated: Jul 27, 2015 |
Number of individuals with the variant: 5
Clinical Features:
elevated CPK enzyme levels (present) , elevated AST and LDH levels (present) , hypertrophic cardiomyopathy (present) , delayed motor milestones (present) , progressive hypotonia (present) … (more)
elevated CPK enzyme levels (present) , elevated AST and LDH levels (present) , hypertrophic cardiomyopathy (present) , delayed motor milestones (present) , progressive hypotonia (present) , dyspnoea (present) , failure-to-thrive (present) , cardiomegaly (present) , patent foramen ovale (present) , pneumonia (present) , absent deep tendon reflexes (present) , wide and low set pinnae (present) , hepatomegaly (present) (less)
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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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Observational clinical study of 22 adult-onset Pompe disease patients undergoing enzyme replacement therapy over 5years. | Stepien KM | Molecular genetics and metabolism | 2016 | PMID: 26873529 |
c.1437G>A intron 9 substitution on acid α-glucosidase gene associated with classic infantile-onset Pompe disease phenotype. | Morales A | BMJ case reports | 2015 | PMID: 26160551 |
Identification and characterization of aberrant GAA pre-mRNA splicing in pompe disease using a generic approach. | Bergsma AJ | Human mutation | 2015 | PMID: 25243733 |
Update of the Pompe disease mutation database with 107 sequence variants and a format for severity rating. | Kroos M | Human mutation | 2008 | PMID: 18425781 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/67c90cfc-e43b-4733-b8ab-02029429e259 | - | - | - | - |
Text-mined citations for rs796051877 ...
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.