ClinVar Genomic variation as it relates to human health
NM_000152.5(GAA):c.377G>A (p.Trp126Ter)
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.377G>A (p.Trp126Ter)
Variation ID: 932904 Accession: VCV000932904.9
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17q25.3 17: 80104963 (GRCh38) [ NCBI UCSC ] 17: 78078762 (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 Jul 16, 2020 Feb 14, 2024 Apr 20, 2020 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000152.5:c.377G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000143.2:p.Trp126Ter nonsense NM_001079803.3:c.377G>A NP_001073271.1:p.Trp126Ter nonsense NM_001079804.3:c.377G>A NP_001073272.1:p.Trp126Ter nonsense NC_000017.11:g.80104963G>A NC_000017.10:g.78078762G>A NG_009822.1:g.8408G>A LRG_673:g.8408G>A - Protein change
- W126*
- Other names
- -
- Canonical SPDI
- NC_000017.11:80104962:G:A
-
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.
-
- Links
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 (2) |
reviewed by expert panel
|
Apr 20, 2020 | RCV001200872.8 |
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 20, 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: SCV001371763.1
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
This variant, c.377G>A (p.Trp126Ter), is a nonsense variant that is predicted to result in nonsense mediated decay and lack of gene product, meeting PVS1. Five … (more)
This variant, c.377G>A (p.Trp126Ter), is a nonsense variant that is predicted to result in nonsense mediated decay and lack of gene product, meeting PVS1. Five individuals with Pompe disease and residual GAA activity meeting PP4 specifications have been reported with this variant (PMIDs 17056254, 25681614). One of these individuals is compound heterozygous for the variant and c.236_246del (p.Pro79ArgfsX13); as the mother is heterozygous for the variant, it is likely that the variants are in trans (PMID 17056254). Another individual is the proband in a family of three siblings with late onset Pompe disease who are all compound heterozygous for the variant and c.-32-13T>G. In addition, two Brazilian siblings are compound heterozygous for the variant and c.1655T>C (p.Leu552Pro) but this in trans data will be used in the classification of p.Leu552Pro and is not included here in order to avoid a circular argument. Finally, an individual with infantile onset Pompe disease appeared to be homozygous for the variant (PMID 17056254). While the mother was heterozygous, the father was neither confirmed to be a carrier, nor appeared to have a deletion. Non-paternity was not ruled out. This data will not be included because the nature of the second variant is unclear. This in trans data meets PM3. An additional case has been reported but was not included because the residual GAA activity was not provided and therefore PP4 cannot be assessed (PMID 19588081). The variant is absent in gnomAD v2.1.1, meeting PM2. There is no ClinVar entry for this variant. In summary, the 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
(Sep 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Glycogen storage disease, type II
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV002238321.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Trp126*) 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.Trp126*) 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: 17056254). ClinVar contains an entry for this variant (Variation ID: 932904). For these reasons, this variant has been classified as Pathogenic. (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 |
---|---|---|---|---|
Novel GAA mutations in patients with Pompe disease. | Turaça LT | Gene | 2015 | PMID: 25681614 |
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 |
Pompe disease in a Brazilian series: clinical and molecular analyses with identification of nine new mutations. | Oba-Shinjo SM | Journal of neurology | 2009 | PMID: 19588081 |
Update of the Pompe disease mutation database with 107 sequence variants and a format for severity rating. | Kroos M | Human mutation | 2008 | PMID: 18425781 |
Pompe disease (glycogen storage disease type II) in Argentineans: clinical manifestations and identification of 9 novel mutations. | Palmer RE | Neuromuscular disorders : NMD | 2007 | PMID: 17056254 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/34cd2c9d-0af8-4990-ae0a-5ee80f34ae19 | - | - | - | - |
Text-mined citations for rs1011631903 ...
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.