VCV000929046.9 - ClinVar

NM_000642.3(AGL):c.4422del (p.Ala1475fs)

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.

(4)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000642.3(AGL):c.4422del (p.Ala1475fs)

Variation ID: 929046 Accession: VCV000929046.9

Type and length

Deletion, 1 bp

Location

Cytogenetic: 1p21.2 1: 99916672 (GRCh38) [ NCBI UCSC ] 1: 100382228 (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	Jun 22, 2020	Feb 14, 2024	Aug 29, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000642.3:c.4422del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000633.2:p.Ala1475fs	frameshift
NM_000028.3:c.4422delT	NP_000019.2:p.Ala1475Glnfs	frameshift
NM_000643.3:c.4422delT	NP_000634.2:p.Ala1475Glnfs	frameshift
NM_000644.3:c.4422delT	NP_000635.2:p.Ala1475Glnfs	frameshift
NM_000646.3:c.4374delT	NP_000637.2:p.Ala1459Glnfs	frameshift
NM_001425325.1:c.4422delT	NP_001412254.1:p.Ala1475Glnfs	frameshift
NM_001425326.1:c.4401delT	NP_001412255.1:p.Ala1468Glnfs	frameshift
NM_001425327.1:c.4221delT	NP_001412256.1:p.Ala1408Glnfs	frameshift
NM_001425328.1:c.4218delT	NP_001412257.1:p.Ala1407Glnfs	frameshift
NM_001425329.1:c.4083delT	NP_001412258.1:p.Ala1362Glnfs	frameshift
NM_001425332.1:c.4044delT	NP_001412261.1:p.Ala1349Glnfs	frameshift
NC_000001.11:g.99916672del
NC_000001.10:g.100382228del
NG_012865.1:g.71589del

... more HGVS ... less HGVS

Protein change

A1459fs, A1475fs

Other names

Canonical SPDI

NC_000001.11:99916671:T:

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.

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

The Genome Aggregation Database (gnomAD), exomes 0.00000

Trans-Omics for Precision Medicine (TOPMed) 0.00003

Links

dbSNP: rs1286364615 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.
AGL		-	-	GRCh38 GRCh37	2675	2695

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.
Glycogen storage disease type III	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Aug 29, 2023	RCV001193899.9

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.
Likely pathogenic (Sep 16, 2019)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Glycogen storage disease type III Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001363065.1 First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020	Publications: PubMed (1) PubMed: 20648714 Comment: Variant summary: AGL c.4422delT (p.Ala1475GlnfsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more) Variant summary: AGL c.4422delT (p.Ala1475GlnfsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation downstream of this position has been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 250766 control chromosomes (gnomAD). c.4422delT has been reported in the literature in an individual affected with Glycogen Storage Disease Type III (Goldstein_2010). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
Pathogenic (Jul 15, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glycogen storage disease type III Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002055512.1 First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022
Pathogenic (Jan 28, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glycogen storage disease type III Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004190950.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Pathogenic (Aug 29, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Glycogen storage disease type III Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001392685.4 First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 20648714‚ 19299494 Comment: For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 929046). 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: 929046). This premature translational stop signal has been observed in individual(s) with clinical features of glycogen storage disease type III (PMID: 20648714). This variant is present in population databases (no rsID available, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Ala1475Glnfs*4) in the AGL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AGL are known to be pathogenic (PMID: 19299494). (less)

Comment:

Variant summary: AGL c.4422delT (p.Ala1475GlnfsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation downstream of this position has been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 250766 control chromosomes (gnomAD). c.4422delT has been reported in the literature in an individual affected with Glycogen Storage Disease Type III (Goldstein_2010). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.

Comment:

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 929046). This premature translational stop signal has been observed in individual(s) with clinical features of glycogen storage disease type III (PMID: 20648714). This variant is present in population databases (no rsID available, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Ala1475Glnfs*4) in the AGL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AGL are known to be pathogenic (PMID: 19299494).

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 analysis of the AGL gene: identification of 25 novel mutations and evidence of genetic heterogeneity in patients with Glycogen Storage Disease Type III.	Goldstein JL	Genetics in medicine : official journal of the American College of Medical Genetics	2010	PMID: 20648714
Distinct mutations in the glycogen debranching enzyme found in glycogen storage disease type III lead to impairment in diverse cellular functions.	Cheng A	Human molecular genetics	2009	PMID: 19299494

Text-mined citations for rs1286364615 ...

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_000642.3(AGL):c.4422del (p.Ala1475fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1286364615 ...