ClinVar Genomic variation as it relates to human health
NM_000152.5(GAA):c.437del (p.Met146fs)
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.437del (p.Met146fs)
Variation ID: 554096 Accession: VCV000554096.13
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 17q25.3 17: 80105023 (GRCh38) [ NCBI UCSC ] 17: 78078822 (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 Aug 5, 2018 Feb 14, 2024 Aug 24, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000152.5:c.437del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000143.2:p.Met146fs frameshift NM_000152.3:c.437delT NM_001079803.3:c.437del NP_001073271.1:p.Met146fs frameshift NM_001079804.3:c.437del NP_001073272.1:p.Met146fs frameshift NC_000017.11:g.80105023del NC_000017.10:g.78078822del NG_009822.1:g.8468del LRG_673:g.8468del LRG_673t1:c.437del - Protein change
- M146fs
- Other names
- NM_000152.5(GAA):c.437del
- p.Met146fs
- Canonical SPDI
- NC_000017.11:80105022: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
Help
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 |
2757 | 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
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
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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 (4) |
reviewed by expert panel
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Aug 24, 2021 | RCV000669662.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 25, 2019 | RCV001785697.5 |
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
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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
(Aug 24, 2021)
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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: SCV002032111.1
First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021 |
Comment:
The NM_000152.5:c.437del (p.Met146ArgfsTer7) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 2/20 leading to nonsense … (more)
The NM_000152.5:c.437del (p.Met146ArgfsTer7) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 2/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The variant was found in compound heterozygosity with a pathogenic variant in two patients who meet the ClinGen LSD VCEP's PP4 specifications; one with c.2237G>A (p.Trp746Ter) (PMID 26693141), and the other with c.2481+102_2646+31del (PMID 22658377)(PP4_Moderate, PM3_Supporting). There is a ClinVar entry for this variant (Variation ID: 554096, 1 star review status) with one submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (specification version 2.0): PVS1, PM2_Supporting, PM3_Supporting, PP4_Moderate. (less)
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Likely pathogenic
(Sep 26, 2017)
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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:
unknown
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Counsyl
Accession: SCV000794438.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Pathogenic
(Jul 04, 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:
unknown
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Baylor Genetics
Accession: SCV004197804.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jun 25, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002021180.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Feb 21, 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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Invitae
Accession: SCV002172567.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains … (more)
Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 554096). This premature translational stop signal has been observed in individuals with Pompe disease (PMID: 29122469). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Met146Argfs*7) 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). 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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Sensitivity of whole exome sequencing in detecting infantile- and late-onset Pompe disease. | Mori M | Molecular genetics and metabolism | 2017 | PMID: 29122469 |
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 |
The impact of antibodies on clinical outcomes in diseases treated with therapeutic protein: lessons learned from infantile Pompe disease. | Banugaria SG | Genetics in medicine : official journal of the American College of Medical Genetics | 2011 | PMID: 21637107 |
Update of the Pompe disease mutation database with 107 sequence variants and a format for severity rating. | Kroos M | Human mutation | 2008 | PMID: 18425781 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/ad8f9e43-3049-4820-8f7a-9b1c912ed389 | - | - | - | - |
Text-mined citations for rs1555598869 ...
HelpRecord last updated Mar 17, 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.