ClinVar Genomic variation as it relates to human health
NM_000152.5(GAA):c.118C>T (p.Arg40Ter)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000152.5(GAA):c.118C>T (p.Arg40Ter)
Variation ID: 426593 Accession: VCV000426593.21
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17q25.3 17: 80104704 (GRCh38) [ NCBI UCSC ] 17: 78078503 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 May 22, 2017 Jun 17, 2024 Apr 6, 2020 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000152.5:c.118C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000143.2:p.Arg40Ter nonsense NM_001079803.3:c.118C>T NP_001073271.1:p.Arg40Ter nonsense NM_001079804.3:c.118C>T NP_001073272.1:p.Arg40Ter nonsense NC_000017.11:g.80104704C>T NC_000017.10:g.78078503C>T NG_009822.1:g.8149C>T LRG_673:g.8149C>T LRG_673t1:c.118C>T - Protein change
- R40*
- Other names
- -
- Canonical SPDI
- NC_000017.11:80104703:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- unknown functional consequence
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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. |
|||
GAA | - | - |
GRCh38 GRCh38 GRCh37 |
2797 | 2848 |
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 20, 2023 | RCV000489843.7 | |
Pathogenic (8) |
reviewed by expert panel
|
Apr 6, 2020 | RCV000589039.17 |
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. |
|
---|---|---|---|---|---|
Pathogenic
(Apr 06, 2020)
|
reviewed by expert panel
Method: curation
|
Glycogen storage disease, type II
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV001371737.1 First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
This nonsense variant, c.118C>T (p.Arg40Ter), is expected to result in a premature termination codon, nonsense mediated decay, and absence of gene product, meeting PVS1. The … (more)
This nonsense variant, c.118C>T (p.Arg40Ter), is expected to result in a premature termination codon, nonsense mediated decay, and absence of gene product, meeting PVS1. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00007 in the South Asian population, meeting PM2. The variant was found in compound heterozygosity with c.-32-13T>G, phase unknown, in two patients with Pompe disease who also meet the ClinGen LSD VCEP's PP4 criterion (PMID 22676651, 22958975), meeting PM3_Supporting. In addition, a large family has been reported with 7 affected siblings who are compound heterozygous for the variant and a variant of unknown significance, c.2647-7G>A (PMID 24107549). Additional cases with this variant have been reported but were not included because residual enzyme activity was not provided and therefore PP4 could not be assessed. There is a ClinVar entry for this variant (Variation ID: 426593, 2 star review status) with two submitters classifying the variant as pathogenic. 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_Supporting, PP4. (less)
|
|
Pathogenic
(Feb 03, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease, type II
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695642.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The c.118C>T variant in GAA is a nonsense mutation. The mutation is predicted to lead to a truncated/absent protein. It has been reported … (more)
Variant summary: The c.118C>T variant in GAA is a nonsense mutation. The mutation is predicted to lead to a truncated/absent protein. It has been reported in multiple affected individuals with Pompe disease, including homozygous pt with classic infantile onset and nearly absent residual enzyme activity. The variant is present in ExAC at low frequency (0.0009%) which does not exceed the maximum frequency for a pathogenic variant in GAA gene (0.42%). Lastly, it has been classified as pathogenic via publications and/or reputable databases/clinical laboratories. Taken together, the variant was classified as Pathogenic. (less)
|
|
Pathogenic
(Nov 22, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000577073.4
First in ClinVar: May 22, 2017 Last updated: Apr 17, 2019 |
Comment:
The R40X pathogenic variant in the GAA gene has been reported previously in multiple individuals with glycogen storage disease type II in the homozygous state, … (more)
The R40X pathogenic variant in the GAA gene has been reported previously in multiple individuals with glycogen storage disease type II in the homozygous state, as well as in the heterozygous state in the presence of a second GAA variant (McCready et al., 2007; Sampaolo et al., 2013; Reuser et al., 1995). Additionally, functional studies in transfected COS cells and patient fibroblast cells showed that R40X resulted in reduced enzyme activity and impacts the function of the protein (Reuser et al., 1995). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. We interpret R40X as a pathogenic variant. (less)
|
|
Pathogenic
(Nov 18, 2019)
|
criteria provided, single submitter
Method: curation
|
Glycogen storage disease, type II
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001422669.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022 |
Comment:
The p.Arg40Ter variant in GAA has been reported in at least 12 individuals (7 Italian, 1 German, 1 French, 1 Portuguese, and 1 Pakistani individuals) … (more)
The p.Arg40Ter variant in GAA has been reported in at least 12 individuals (7 Italian, 1 German, 1 French, 1 Portuguese, and 1 Pakistani individuals) with Glycogen Storage Disease II, segregated with disease in 7 affected relatives from 1 family (PMID: 17723315, 9266392, 22676651, 11071489, 20559845, 24107549), and has been identified in 0.001% (4/275242) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs767409395). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported pathogenic in ClinVar by GeneDx and Integrated Genetics/Laboratory Corporation of America (Variation ID: 426593). This nonsense variant leads to a premature termination codon at position 40, which is predicted to lead to a truncated or absent protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive Glycogen Storage Disease II. The presence of this variant in combination with a reported pathogenic variant and in the homozygous state in individuals with Glycogen Storage Disease II increases the likelihood that the p.Arg40Ter variant is pathogenic (PMID: 17723315, 22958975, 22676651). The phenotype of individuals homozygous and compound heterozygous for this variant is highly specific for Glycogen Storage Disease II based on low relative GAA activity consistent with disease (PMID: 22676651, 22958975, 24107549, 17723315). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on the predicted impact of this variant and multiple occurrences with pathogenic variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PVS1, PM3, PP4, PM2 (Richards 2015). (less)
|
|
Pathogenic
(Apr 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease, type II
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Servicio Canario de Salud, Hospital Universitario Nuestra Sra. de Candelaria
Accession: SCV002758770.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
Comment:
The c.118C>T (p.Arg40Ter) in compound heterocigosity with c.-32-13T>G GAA variant has been reported in our laboratory in a 52-year-old woman from England with diagnosis of … (more)
The c.118C>T (p.Arg40Ter) in compound heterocigosity with c.-32-13T>G GAA variant has been reported in our laboratory in a 52-year-old woman from England with diagnosis of Pompe disease (onset 10 years before) with parents and four asymptomatic children and alpha-1,4-glucosidase lysosomal enzyme activity study: 0.4 µmol/L/h (cut-off value: >2.0). Pompe Variant Database describes this phenotype in eight patients, all diagnosed between the ages of 20 and 60. It has been previously reported in patients with Pompe disease both in the homozygous and heterozygous state (PMID: 17723315, 24107549, 7603530, 29124014, 9266392, 22676651, 11071489, 20559845, 22958975). This variant is present in population databases (gnomAD allele frequency 0.00001428). ClinVar contains an entry for this variant (Variation ID: 426593) reviewed by expert panel. Functional studies in transfected COS cells and patient fibroblast cells showed that R40X resulted in reduced enzyme activity and impacts the function of the protein (PMID: 24150945). In summary, c.118C>T (p.Arg40Ter) GAA variant meets our criteria to be classified as pathogenic for Pompe disease in an autosomal recessive manner based upon functional evidence and its identification in numerous affected individuals. (less)
Indication for testing: OMIM#232300 Glycogen storage disease II
Age: 50-59 years
Sex: female
Ethnicity/Population group: caucasian
Geographic origin: England
|
|
Pathogenic
(Sep 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease, type II
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002791870.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
Pathogenic
(Oct 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002023792.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Jan 03, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease, type II
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001587223.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg40*) 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.Arg40*) 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 present in population databases (rs767409395, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with Pompe disease (PMID: 24107549, 29124014). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 426593). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Mar 07, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease, type II
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV005058733.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
|
|
Pathogenic
(Nov 30, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Glycogen storage disease type II
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002091889.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
---|---|---|---|---|
unknown functional consequence
|
Servicio Canario de Salud, Hospital Universitario Nuestra Sra. de Candelaria
Accession: SCV002758770.1
|
|
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
A New Integrated Newborn Screening Workflow Can Provide a Shortcut to Differential Diagnosis and Confirmation of Inherited Metabolic Diseases. | Ko JM | Yonsei medical journal | 2018 | PMID: 29869463 |
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 |
Clinical and molecular genetic study of infantile-onset Pompe disease in Chinese patients: identification of 6 novel mutations. | Fu L | Gene | 2014 | PMID: 24269976 |
Distinct disease phenotypes linked to different combinations of GAA mutations in a large late-onset GSDII sibship. | Sampaolo S | Orphanet journal of rare diseases | 2013 | PMID: 24107549 |
Auditory system involvement in late onset Pompe disease: a study of 20 Italian patients. | Musumeci O | Molecular genetics and metabolism | 2012 | PMID: 22958975 |
A cross-sectional single-centre study on the spectrum of Pompe disease, German patients: molecular analysis of the GAA gene, manifestation and genotype-phenotype correlations. | Herzog A | Orphanet journal of rare diseases | 2012 | PMID: 22676651 |
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 |
Abnormalities of cerebral arteries are frequent in patients with late-onset Pompe disease. | Sacconi S | Journal of neurology | 2010 | PMID: 20559845 |
Update of the Pompe disease mutation database with 107 sequence variants and a format for severity rating. | Kroos M | Human mutation | 2008 | PMID: 18425781 |
Development of a clinical assay for detection of GAA mutations and characterization of the GAA mutation spectrum in a Canadian cohort of individuals with glycogen storage disease, type II. | McCready ME | Molecular genetics and metabolism | 2007 | PMID: 17723315 |
Juvenile and adult-onset acid maltase deficiency in France: genotype-phenotype correlation. | Laforêt P | Neurology | 2000 | PMID: 11071489 |
A novel acid alpha-glucosidase mutation identified in a Pakistani family with glycogen storage disease type II. | Kroos MA | Journal of inherited metabolic disease | 1997 | PMID: 9266392 |
Glycogenosis type II (acid maltase deficiency). | Reuser AJ | Muscle & nerve. Supplement | 1995 | PMID: 7603530 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/79019119-b26c-4336-8958-b3272cd7e778 | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/b83bdb13-e262-4abd-a20a-ab659995e215 | - | - | - | - |
click to load more click to collapse |
Text-mined citations for rs767409395 ...
HelpRecord last updated Jun 23, 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.