Variant summary: GAA c.[752C>T;761C>T] (p.[Ser251Leu;Ser254Leu]) variant is a complex allele and involves the alteration of multiple nucleotides. The variant allele was found at a frequency of 0.00021 in 251124 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (0.00021 vs 0.0042), allowing no conclusion about variant significance. c.[752C>T;761C>T] has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) in homozygous and compound heterozygous state (e.g. Labrousse_2010, Chien_2011, Liao_2014, Fukuhara_2018). These data indicate that the variant is likely to be associated with disease. Multiple publications report that this complex allele results in enzyme activity of <10% in homozygous patients (Labrousse_2010, Chien_2011, Fukuhara_2018). ClinVar submitters cite the two variants separately with conflicting assessments (Variation IDs: 325781, 325782). At least one clinical diagnostic laboratory classified this complex allele as pathogenic (SCV000626639.5). Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000152.5(GAA):c.[752C>T;761C>T]
Germline
Classification
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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.
(1)
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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.
Pathogenic
1
criteria provided, single submitter
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
This haplotype includes the following variants
NM_000152.5(GAA):c.[752C>T;761C>T]
- Other names
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- Functional consequence
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- Links
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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 |
2805 | 2857 | |
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 (1) |
criteria provided, single submitter
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Dec 5, 2022 | RCV001779452.5 |
Submissions - Germline
| Classification
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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
(Dec 05, 2022)
|
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: SCV002014857.3
First in ClinVar: Nov 20, 2021 Last updated: Nov 11, 2023 |
Comment:
Variant summary: GAA c.[752C>T;761C>T] (p.[Ser251Leu;Ser254Leu]) variant is a complex allele and involves the alteration of multiple nucleotides. The variant allele was found at a frequency … (more)
Variant summary: GAA c.[752C>T;761C>T] (p.[Ser251Leu;Ser254Leu]) variant is a complex allele and involves the alteration of multiple nucleotides. The variant allele was found at a frequency of 0.00021 in 251124 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (0.00021 vs 0.0042), allowing no conclusion about variant significance. c.[752C>T;761C>T] has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) in homozygous and compound heterozygous state (e.g. Labrousse_2010, Chien_2011, Liao_2014, Fukuhara_2018). These data indicate that the variant is likely to be associated with disease. Multiple publications report that this complex allele results in enzyme activity of <10% in homozygous patients (Labrousse_2010, Chien_2011, Fukuhara_2018). ClinVar submitters cite the two variants separately with conflicting assessments (Variation IDs: 325781, 325782). At least one clinical diagnostic laboratory classified this complex allele as pathogenic (SCV000626639.5). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
Comment:
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. |
Comment:
Variant summary: GAA c.[752C>T;761C>T] (p.[Ser251Leu;Ser254Leu]) variant is a complex allele and involves the alteration of multiple nucleotides. The variant allele was found at a frequency of 0.00021 in 251124 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (0.00021 vs 0.0042), allowing no conclusion about variant significance. c.[752C>T;761C>T] has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) in homozygous and compound heterozygous state (e.g. Labrousse_2010, Chien_2011, Liao_2014, Fukuhara_2018). These data indicate that the variant is likely to be associated with disease. Multiple publications report that this complex allele results in enzyme activity of <10% in homozygous patients (Labrousse_2010, Chien_2011, Fukuhara_2018). ClinVar submitters cite the two variants separately with conflicting assessments (Variation IDs: 325781, 325782). At least one clinical diagnostic laboratory classified this complex allele as pathogenic (SCV000626639.5). Based on the evidence outlined above, the variant was classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Diagnostic delay in late-onset Pompe disease among Chinese patients: A retrospective study. | Yue D | JIMD reports | 2023 | PMID: 38186848 |
| Diagnostic delay in late-onset Pompe disease among Chinese patients: A retrospective study. | Yue D | JIMD reports | 2023 | PMID: 38186848 |
| Establishment of Cutoff Values for Newborn Screening of Six Lysosomal Storage Disorders by Tandem Mass Spectrometry. | Li R | Frontiers in pediatrics | 2022 | PMID: 35419325 |
| Comprehensive analysis of recessive carrier status using exome and genome sequencing data in 1543 Southern Chinese. | Chau JFT | NPJ genomic medicine | 2022 | PMID: 35314707 |
| Outcome of Later-Onset Pompe Disease Identified Through Newborn Screening. | Lee NC | The Journal of pediatrics | 2022 | PMID: 34995642 |
| The First Year Experience of Newborn Screening for Pompe Disease in California. | Tang H | International journal of neonatal screening | 2020 | PMID: 33073007 |
| The First Year Experience of Newborn Screening for Pompe Disease in California. | Tang H | International journal of neonatal screening | 2020 | PMID: 33073007 |
| A Comparative Effectiveness Study of Newborn Screening Methods for Four Lysosomal Storage Disorders. | Sanders KA | International journal of neonatal screening | 2020 | PMID: 32802993 |
| Earlier and higher dosing of alglucosidase alfa improve outcomes in patients with infantile-onset Pompe disease: Evidence from real-world experiences. | Chien YH | Molecular genetics and metabolism reports | 2020 | PMID: 32373469 |
| Newborn screening for Morquio disease and other lysosomal storage diseases: results from the 8-plex assay for 70,000 newborns. | Chien YH | Orphanet journal of rare diseases | 2020 | PMID: 32014045 |
| Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging. | Hou YC | Proceedings of the National Academy of Sciences of the United States of America | 2020 | PMID: 31980526 |
| Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging. | Hou YC | Proceedings of the National Academy of Sciences of the United States of America | 2020 | PMID: 31980526 |
| Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging. | Hou YC | Proceedings of the National Academy of Sciences of the United States of America | 2020 | PMID: 31980526 |
| Implementation of a Targeted Next-Generation Sequencing Panel for Constitutional Newborn Screening in High-Risk Neonates. | Lee H | Yonsei medical journal | 2019 | PMID: 31637888 |
| Implementation of a Targeted Next-Generation Sequencing Panel for Constitutional Newborn Screening in High-Risk Neonates. | Lee H | Yonsei medical journal | 2019 | PMID: 31637888 |
| Implementation of a Targeted Next-Generation Sequencing Panel for Constitutional Newborn Screening in High-Risk Neonates. | Lee H | Yonsei medical journal | 2019 | PMID: 31637888 |
| Newborn screening: Taiwanese experience. | Chien YH | Annals of translational medicine | 2019 | PMID: 31392193 |
| Gene-specific features enhance interpretation of mutational impact on acid α-glucosidase enzyme activity. | Adhikari AN | Human mutation | 2019 | PMID: 31228295 |
| Gene-specific features enhance interpretation of mutational impact on acid α-glucosidase enzyme activity. | Adhikari AN | Human mutation | 2019 | PMID: 31228295 |
| Newborn screening for Pompe disease in Japan: report and literature review of mutations in the GAA gene in Japanese and Asian patients. | Momosaki K | Journal of human genetics | 2019 | PMID: 31076647 |
| Newborn screening for Pompe disease in Japan: report and literature review of mutations in the GAA gene in Japanese and Asian patients. | Momosaki K | Journal of human genetics | 2019 | PMID: 31076647 |
| Identification of Seven Novel Mutations in the Acid Alpha-glucosidase Gene in Five Chinese Patients with Late-onset Pompe Disease. | Liu HX | Chinese medical journal | 2018 | PMID: 29451150 |
| 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 |
| 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 |
| 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 |
| Sensitivity of whole exome sequencing in detecting infantile- and late-onset Pompe disease. | Mori M | Molecular genetics and metabolism | 2017 | PMID: 29122469 |
| Sensitivity of whole exome sequencing in detecting infantile- and late-onset Pompe disease. | Mori M | Molecular genetics and metabolism | 2017 | PMID: 29122469 |
| Mass Spectrometry but Not Fluorimetry Distinguishes Affected and Pseudodeficiency Patients in Newborn Screening for Pompe Disease. | Liao HC | Clinical chemistry | 2017 | PMID: 28450385 |
| Mass Spectrometry but Not Fluorimetry Distinguishes Affected and Pseudodeficiency Patients in Newborn Screening for Pompe Disease. | Liao HC | Clinical chemistry | 2017 | PMID: 28450385 |
| Liquid Chromatography-Tandem Mass Spectrometry Assay of Leukocyte Acid α-Glucosidase for Post-Newborn Screening Evaluation of Pompe Disease. | Lin N | Clinical chemistry | 2017 | PMID: 28196920 |
| Liquid Chromatography-Tandem Mass Spectrometry Assay of Leukocyte Acid α-Glucosidase for Post-Newborn Screening Evaluation of Pompe Disease. | Lin N | Clinical chemistry | 2017 | PMID: 28196920 |
| Slow, progressive myopathy in neonatally treated patients with infantile-onset Pompe disease: a muscle magnetic resonance imaging study. | Peng SS | Orphanet journal of rare diseases | 2016 | PMID: 27183828 |
| Slow, progressive myopathy in neonatally treated patients with infantile-onset Pompe disease: a muscle magnetic resonance imaging study. | Peng SS | Orphanet journal of rare diseases | 2016 | PMID: 27183828 |
| Long-term prognosis of patients with infantile-onset Pompe disease diagnosed by newborn screening and treated since birth. | Chien YH | The Journal of pediatrics | 2015 | PMID: 25466677 |
| Long-term prognosis of patients with infantile-onset Pompe disease diagnosed by newborn screening and treated since birth. | Chien YH | The Journal of pediatrics | 2015 | PMID: 25466677 |
| Detecting multiple lysosomal storage diseases by tandem mass spectrometry--a national newborn screening program in Taiwan. | Liao HC | Clinica chimica acta; international journal of clinical chemistry | 2014 | PMID: 24513544 |
| Detecting multiple lysosomal storage diseases by tandem mass spectrometry--a national newborn screening program in Taiwan. | Liao HC | Clinica chimica acta; international journal of clinical chemistry | 2014 | PMID: 24513544 |
| Detecting multiple lysosomal storage diseases by tandem mass spectrometry--a national newborn screening program in Taiwan. | Liao HC | Clinica chimica acta; international journal of clinical chemistry | 2014 | PMID: 24513544 |
| Update of the pompe disease mutation database with 60 novel GAA sequence variants and additional studies on the functional effect of 34 previously reported variants. | Kroos M | Human mutation | 2012 | PMID: 22644586 |
| Update of the pompe disease mutation database with 60 novel GAA sequence variants and additional studies on the functional effect of 34 previously reported variants. | Kroos M | Human mutation | 2012 | PMID: 22644586 |
| Later-onset Pompe disease: early detection and early treatment initiation enabled by newborn screening. | Chien YH | The Journal of pediatrics | 2011 | PMID: 21232767 |
| Later-onset Pompe disease: early detection and early treatment initiation enabled by newborn screening. | Chien YH | The Journal of pediatrics | 2011 | PMID: 21232767 |
| Later-onset Pompe disease: early detection and early treatment initiation enabled by newborn screening. | Chien YH | The Journal of pediatrics | 2011 | PMID: 21232767 |
| Genetic heterozygosity and pseudodeficiency in the Pompe disease newborn screening pilot program. | Labrousse P | Molecular genetics and metabolism | 2010 | PMID: 20080426 |
| Genetic heterozygosity and pseudodeficiency in the Pompe disease newborn screening pilot program. | Labrousse P | Molecular genetics and metabolism | 2010 | PMID: 20080426 |
| Genetic heterozygosity and pseudodeficiency in the Pompe disease newborn screening pilot program. | Labrousse P | Molecular genetics and metabolism | 2010 | PMID: 20080426 |
| 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 |
| 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 |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/36f5295f-17ef-4108-9f5e-ff7bb3e8ee5c | - | - | - | - |
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Text-mined citations for this variant ...
HelpRecord last updated Oct 27, 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.