VCV000255363.21 - ClinVar

NM_000152.5(GAA):c.547-39T>G

Germline

Classification

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.

(9)

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.

Benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000152.5(GAA):c.547-39T>G

Variation ID: 255363 Accession: VCV000255363.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q25.3 17: 80105710 (GRCh38) [ NCBI UCSC ] 17: 78079509 (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	Oct 3, 2016	Sep 29, 2024	Jan 29, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000152.5:c.547-39T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001079803.3:c.547-39T>G		intron variant
NM_001079804.3:c.547-39T>G		intron variant
NC_000017.11:g.80105710T>G
NC_000017.10:g.78079509T>G
NG_009822.1:g.9155T>G
LRG_673:g.9155T>G
LRG_673t1:c.547-39T>G

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000017.11:80105709:T:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.39437 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.60353

1000 Genomes Project 0.60563

Trans-Omics for Precision Medicine (TOPMed) 0.63796

The Genome Aggregation Database (gnomAD) 0.65696

The Genome Aggregation Database (gnomAD), exomes 0.66798

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.66915

Exome Aggregation Consortium (ExAC) 0.67576

Links

ClinGen: CA8814921 dbSNP: rs12452721 VarSome

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
Gene	OMIM	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	2805	2857

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.
not specified	Benign (4)	criteria provided, multiple submitters, no conflicts	Aug 7, 2017	RCV000246553.11
Glycogen storage disease, type II	Benign (3)	criteria provided, multiple submitters, no conflicts	Jan 29, 2024	RCV001249010.12
not provided	Benign (2)	criteria provided, multiple submitters, no conflicts	Dec 5, 2018	RCV001651108.3

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.
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000302689.1 First in ClinVar: Oct 03, 2016 Last updated: Oct 03, 2016
Benign (Aug 07, 2017)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000856219.1 First in ClinVar: Oct 03, 2016 Last updated: Oct 03, 2016	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GAA Number of individuals with the variant: 15 Sex: mixed
Benign (Jun 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glycogen storage disease, type II Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001738008.1 First in ClinVar: Jun 24, 2021 Last updated: Jun 24, 2021	Sex: mixed
Benign (Dec 05, 2018)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001869756.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021	Comment: This variant is associated with the following publications: (PMID: 30595407, 24008937, 25681614, 28032299)
Benign (Jan 22, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) 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: SCV001422857.2 First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022	Publications: PubMed (1) PubMed: 17915575 Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/df85d886-fa85-4745-a3e3-aad6119a2872 Comment: The c.547-39T>G variant in GAA has been reported in at least 6 individuals with suspected glycogen storage disease II (PMID: 28032299, 25681614), and has also … (more) The c.547-39T>G variant in GAA has been reported in at least 6 individuals with suspected glycogen storage disease II (PMID: 28032299, 25681614), and has also been reported in ClinVar (VariationID: 255363) as benign by EGL Genetic Diagnostics and PreventionGenetics. This variant has been identified in 77.9% (8028/10312) of Ashkenazi Jewish chromosomes, including 3120 homozygotes, and is present at high frequencies in other populations, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs12452721). This variant has been seen in the general population at a frequency high enough to rule out a pathogenic role. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, this variant meets criteria to be classified as benign for glycogen storage disease II in an autosomal recessive manner based on high frequency in the general population. ACMG/AMP Criteria applied: BA1, BP7, BP4 (Richards 2015). (less)
Benign (Jan 29, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Glycogen storage disease, type II Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001725516.4 First in ClinVar: Jun 15, 2021 Last updated: Feb 20, 2024
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005248717.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001930052.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001954241.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021

Comment:

The c.547-39T>G variant in GAA has been reported in at least 6 individuals with suspected glycogen storage disease II (PMID: 28032299, 25681614), and has also been reported in ClinVar (VariationID: 255363) as benign by EGL Genetic Diagnostics and PreventionGenetics. This variant has been identified in 77.9% (8028/10312) of Ashkenazi Jewish chromosomes, including 3120 homozygotes, and is present at high frequencies in other populations, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs12452721). This variant has been seen in the general population at a frequency high enough to rule out a pathogenic role. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, this variant meets criteria to be classified as benign for glycogen storage disease II in an autosomal recessive manner based on high frequency in the general population. ACMG/AMP Criteria applied: BA1, BP7, BP4 (Richards 2015).

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Molecular genetics of late onset glycogen storage disease II in Italy.	Pittis MG	Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology	2007	PMID: 17915575
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GAA	-	-	-	-
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/df85d886-fa85-4745-a3e3-aad6119a2872	-	-	-	-

Text-mined citations for rs12452721 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000152.5(GAA):c.547-39T>G

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs12452721 ...