ClinVar Genomic variation as it relates to human health
NM_000152.5(GAA):c.722_723del (p.Phe241fs)
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.722_723del (p.Phe241fs)
Variation ID: 932903 Accession: VCV000932903.10
- Type and length
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Deletion, 2 bp
- Location
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Cytogenetic: 17q25.3 17: 80107585-80107586 (GRCh38) [ NCBI UCSC ] 17: 78081384-78081385 (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 16, 2020 Feb 14, 2024 Jan 21, 2020 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000152.5:c.722_723del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000143.2:p.Phe241fs frameshift NM_000152.4:c.722_723delTT NM_001079803.3:c.722_723del NP_001073271.1:p.Phe241fs frameshift NM_001079804.3:c.722_723del NP_001073272.1:p.Phe241fs frameshift NC_000017.11:g.80107586_80107587del NC_000017.10:g.78081385_78081386del NG_009822.1:g.11031_11032del LRG_673:g.11031_11032del - Protein change
- F241fs
- Other names
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- Canonical SPDI
- NC_000017.11:80107584:TTT: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 |
2754 | 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
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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 (3) |
reviewed by expert panel
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Jan 21, 2020 | RCV001200871.9 |
Submissions - Germline
Classification
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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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Pathogenic
(Jan 21, 2020)
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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
Accession: SCV001371761.1
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
This variant, c.722_723del (p.Phe241CysfsTer), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene … (more)
This variant, c.722_723del (p.Phe241CysfsTer), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product. Therefore, PVS1 can be applied. This variant is absent in gnomAD v2.1.1, meeting PM2. It has been found in at least two patients with Pompe disease who meet the ClinGen LSD VCEP's specifications for PP4 (PMID 19775921). One of these patients is compound heterozygous for the variant and c.1687C>T (p.Gln563Ter), and the other is compound heterozygous for the variant and c.1754+1G>A. In both cases, the variants were confirmed to be in trans. This data meets PM3_Strong. Additional cases have been reported, but did not meet PP4 (PMID 28838325). There is no ClinVar entry for this variant. In summary, this 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: PVS1, PM2, PM3_Strong, PP4. (less)
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Pathogenic
(Sep 26, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002598558.1
First in ClinVar: Nov 05, 2022 Last updated: Nov 05, 2022 |
Comment:
Variant summary: GAA c.722_723delTT (p.Phe241CysfsX88) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: GAA c.722_723delTT (p.Phe241CysfsX88) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251118 control chromosomes. c.722_723delTT has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease; examples: Kishnani_2010, Bali_2012, Kroos_2008, etc). These data indicate that the variant is likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Oct 25, 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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Invitae
Accession: SCV002196654.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Phe241Cysfs*88) in the GAA gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Phe241Cysfs*88) in the GAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Pompe disease (PMID: 11949932, 18425781). This variant is also known as c.721_722delTT. ClinVar contains an entry for this variant (Variation ID: 932903). For these reasons, this variant has been classified as Pathogenic. (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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A study on the safety and efficacy of reveglucosidase alfa in patients with late-onset Pompe disease. | Byrne BJ | Orphanet journal of rare diseases | 2017 | PMID: 28838325 |
CRIM-negative infantile Pompe disease: characterization of immune responses in patients treated with ERT monotherapy. | Berrier KL | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741864 |
Transcriptional response to GAA deficiency (Pompe disease) in infantile-onset patients. | Palermo AT | Molecular genetics and metabolism | 2012 | PMID: 22658377 |
Persistence of high sustained antibodies to enzyme replacement therapy despite extensive immunomodulatory therapy in an infant with Pompe disease: need for agents to target antibody-secreting plasma cells. | Banugaria SG | Molecular genetics and metabolism | 2012 | PMID: 22365055 |
Predicting cross-reactive immunological material (CRIM) status in Pompe disease using GAA mutations: lessons learned from 10 years of clinical laboratory testing experience. | Bali DS | American journal of medical genetics. Part C, Seminars in medical genetics | 2012 | PMID: 22252923 |
Cross-reactive immunologic material status affects treatment outcomes in Pompe disease infants. | Kishnani PS | Molecular genetics and metabolism | 2010 | PMID: 19775921 |
Update of the Pompe disease mutation database with 107 sequence variants and a format for severity rating. | Kroos M | Human mutation | 2008 | PMID: 18425781 |
Acid alpha-glucosidase deficiency (glycogenosis type II, Pompe disease). | Raben N | Current molecular medicine | 2002 | PMID: 11949932 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/1b742d4e-033e-469e-b02a-e368ad095141 | - | - | - | - |
Text-mined citations for rs2039116471 ...
HelpRecord last updated Feb 14, 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.