ClinVar Genomic variation as it relates to human health
NM_000152.5(GAA):c.1826dup (p.Tyr609Ter)
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
-
NM_000152.5(GAA):c.1826dup (p.Tyr609Ter)
Variation ID: 189144 Accession: VCV000189144.23
- Type and length
-
Duplication, 1 bp
- Location
-
Cytogenetic: 17q25.3 17: 80112648-80112649 (GRCh38) [ NCBI UCSC ] 17: 78086447-78086448 (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 Mar 29, 2015 Feb 14, 2024 Feb 14, 2020 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000152.5(GAA):c.1826dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000152.5:c.1826dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000143.2:p.Tyr609Ter nonsense NM_000152.3:c.1826dup NM_001079803.3:c.1826dup NP_001073271.1:p.Tyr609Ter nonsense NM_001079804.3:c.1826dup NP_001073272.1:p.Tyr609Ter nonsense NC_000017.11:g.80112649dup NC_000017.10:g.78086448dup NG_009822.1:g.16094dup LRG_673:g.16094dup LRG_673t1:c.1826dup - Protein change
- Y609*
- Other names
- -
- Canonical SPDI
- NC_000017.11:80112648:A:AA
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 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 |
2754 | 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
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 (5) |
reviewed by expert panel
|
Feb 14, 2020 | RCV000169565.16 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jul 25, 2023 | RCV000727554.9 |
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
(Feb 14, 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
Accession: SCV001371766.1
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
This variant, c.1826dup (p.Tyr609Terfs), is predicted to cause a frameshift, premature termination codon, and nonsense mediated decay resulting in lack of gene product. This is … (more)
This variant, c.1826dup (p.Tyr609Terfs), is predicted to cause a frameshift, premature termination codon, and nonsense mediated decay resulting in lack of gene product. This is supported by the absence of cross-reactive immunological material in cultured fibroblasts from a patient with the variant (PMID 22252923). Therefore, PVS1 can be applied. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001816 in the European non-Finnish population, meeting PM2. Two individuals meeting the ClinGen LSD VCEP's specifications for PP4 have been reported who are compound heterozygous for the variant and a unique pathogenic variant; one of these patients is compound heterozygous for the variant and c.525delT, and the other patient is compound heterozygous for the variant and c.2238G>A (p.Trp746Ter) (PMIDs 12897283, 25741864). Therefore, PP4 and PM3 can be applied. Another patient was reported who is compound heterozygous for this variant and a known pathogenic variant (c.525delT), but this data was not included because the GAA activity for the patient was not reported (PMID 14695532). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP: PVS1, PM2, PM3, PP4. (less)
|
|
Pathogenic
(Aug 20, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000854784.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Number of individuals with the variant: 2
Sex: mixed
|
|
Pathogenic
(Jan 22, 2020)
|
criteria provided, single submitter
Method: curation
|
Glycogen storage disease, type II
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Broad Institute Rare Disease Group, Broad Institute
Accession: SCV001422877.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022 |
Comment:
The p.Tyr609Ter variant in GAA has been reported in at least 4 individuals (including at least 1 Dutch individual) with Glycogen Storage Disease II (PMID: … (more)
The p.Tyr609Ter variant in GAA has been reported in at least 4 individuals (including at least 1 Dutch individual) with Glycogen Storage Disease II (PMID: 14695532, 12897283, 25741864, 22252923), and has also been reported likely pathogenic by Counsyl and pathogenic by EGL Genetic Diagnostics in ClinVar (Variation ID: 189144). This variant has been identified in 0.00002% (2/110126) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs778892297). 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 leads to a premature termination codon at position 609, 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 reported pathogenic variants and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Tyr609Ter variant is pathogenic (PMID: 25741864, 12897283). Another pathogenic variant, c.1827delC (p.Tyr609Ter), has been reported with the same position and amino acid change (PMID: 14695532, 26693141). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on multiple reports of this variant in CRIM-negative cohorts and abnormally low GAA activity detected in the fibroblasts of one individual heterozygous for this variant (PMID: 22252923, 25741864, 12897283). 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 the variant and multiple occurrences with pathogenic GAA variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PVS1, PM3, PM2, PP4 (Richards 2015). (less)
|
|
Likely pathogenic
(Jan 22, 2015)
|
criteria provided, single submitter
Method: literature only
|
Glycogen storage disease, type II
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000221062.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
|
|
Pathogenic
(Jul 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002571489.3
First in ClinVar: Sep 17, 2022 Last updated: Aug 05, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect via a mouse model homozygous knock-in for the … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect via a mouse model homozygous knock-in for the p.(Y609X) variant that has features of Infantile-onset Pompe Disease (IOPD) (Huang et al., 2020); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31254424, 33301762, 12897283, 25846667, 29124014, 32587263) (less)
|
|
Pathogenic
(Jan 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease, type II
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004197871.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
Pathogenic
(Jun 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease, type II
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001228766.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 189144). This premature translational stop signal … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 189144). This premature translational stop signal has been observed in individual(s) with Pompe disease (PMID: 12897283, 24269976, 25846667, 29124014). This variant is present in population databases (rs754952153, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Tyr609*) 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). (less)
|
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 |
---|---|---|---|---|
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 |
Novel presentation of Pompe disease: Inclusion-body myositis-like clinical phenotype. | Bandyopadhyay S | Muscle & nerve | 2015 | PMID: 25846667 |
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 |
Clinical and molecular genetic study of infantile-onset Pompe disease in Chinese patients: identification of 6 novel mutations. | Fu L | Gene | 2014 | PMID: 24269976 |
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 |
Update of the Pompe disease mutation database with 107 sequence variants and a format for severity rating. | Kroos M | Human mutation | 2008 | PMID: 18425781 |
Twenty-two novel mutations in the lysosomal alpha-glucosidase gene (GAA) underscore the genotype-phenotype correlation in glycogen storage disease type II. | Hermans MM | Human mutation | 2004 | PMID: 14695532 |
The natural course of infantile Pompe's disease: 20 original cases compared with 133 cases from the literature. | van den Hout HM | Pediatrics | 2003 | PMID: 12897283 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GAA | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/a5027f68-b5a5-4555-bbd9-5d3e00d003fb | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/f17c6338-2255-4ce6-93e0-2e1565023eec | - | - | - | - |
click to load more click to collapse |
Text-mined citations for rs786204727 ...
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.