VCV000011992.13 - ClinVar

NM_002863.5(PYGL):c.1768+1G>A

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic

5 out of 7 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002863.5(PYGL):c.1768+1G>A

Variation ID: 11992 Accession: VCV000011992.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q22.1 14: 50912155 (GRCh38) [ NCBI UCSC ] 14: 51378873 (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	Apr 4, 2013	Feb 25, 2025	Mar 17, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_002863.5:c.1768+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001163940.2:c.1666+1G>A		splice donor
NC_000014.9:g.50912155C>T
NC_000014.8:g.51378873C>T
NG_012796.1:g.37376G>A

... more HGVS ... less HGVS

Protein change

Other names

IVS14DS, G-A, +1

Canonical SPDI

NC_000014.9:50912154:C: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.

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00004

Links

ClinGen: CA341169 OMIM: 613741.0001 dbSNP: rs113993982 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.
PYGL		-	-	GRCh38 GRCh37	375	395

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 VI	Pathogenic (7)	criteria provided, multiple submitters, no conflicts	Mar 17, 2024	RCV000012772.17

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 (Jul 27, 2020) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glycogen storage disease, type VI Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001522876.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Pathogenic (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glycogen storage disease, type VI Affected status: yes Allele origin: germline	Pathology and Clinical Laboratory Medicine, King Fahad Medical City Accession: SCV000996283.1 First in ClinVar: Oct 19, 2019 Last updated: Oct 19, 2019	Number of individuals with the variant: 6 Ethnicity/Population group: Arab Geographic origin: Middle East
Pathogenic (Sep 01, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glycogen storage disease, type VI Affected status: yes Allele origin: germline	3billion, Medical Genetics Accession: SCV002573001.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). Canonical splice site is predicted to alter … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). Canonical splice site is predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000011992). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Hepatomegaly (present) , Elevated circulating hepatic transaminase concentration (present) Zygosity: Homozygote
Pathogenic (Mar 17, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Glycogen storage disease, type VI Affected status: unknown Allele origin: germline	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre Accession: SCV004804946.2 First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024
Pathogenic (Feb 23, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Glycogen storage disease, type VI Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000819606.5 First in ClinVar: Oct 10, 2018 Last updated: Feb 25, 2025	Publications: PubMed (3) PubMed: 28492532‚ 9529348‚ 32892177 Comment: This sequence change affects a donor splice site in intron 14 of the PYGL gene. RNA analysis indicates that disruption of this splice site induces … (more) This sequence change affects a donor splice site in intron 14 of the PYGL gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs113993982, gnomAD 0.006%). Disruption of this splice site has been observed in individuals with glycogen storage disease type VI (PMID: 9529348, 32892177). ClinVar contains an entry for this variant (Variation ID: 11992). Studies have shown that disruption of this splice site results in 3 aberrantly spliced mRNAs and introduces a premature termination codon (PMID: 9529348). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Apr 01, 1998) N Not contributing to aggregate classification	no assertion criteria provided Method: literature only	GLYCOGEN STORAGE DISEASE VI Affected status: not provided Allele origin: germline	OMIM Accession: SCV000033007.2 First in ClinVar: Apr 04, 2013 Last updated: May 05, 2014	Publications: PubMed (1) PubMed: 9529348 Comment on evidence: In a 4.5-year-old boy with glycogen storage disease VI (GSD6; 232700), the son of first-cousin Israeli-Arab Bedouin parents, Burwinkel et al. (1998) described a splice … (more) In a 4.5-year-old boy with glycogen storage disease VI (GSD6; 232700), the son of first-cousin Israeli-Arab Bedouin parents, Burwinkel et al. (1998) described a splice site mutation. The patient presented at 2 years of age with hepatomegaly and growth retardation, but had no clinical history of fasting hypoglycemia. He was found to be homozygous for an insertion of 119 nucleotides in codon R589, resulting in a frameshift and introducing a stop codon after 5 missense codons. Sequencing showed that the insert was an intron, presumably intron 14, but with a G-to-A replacement in the GT consensus dinucleotide of the 5-prime splice site. This splice site mutation thus led to the retention of intron 14 and 2 aberrant splice products employing neighboring GT dinucleotides in exon 14 and in intron 14, respectively, as illegitimate 5-prime splice sites. Both parents were heterozygous for the mutation. (less)
not provided (-) N Not contributing to aggregate classification	no classification provided Method: literature only	Glycogen storage disease, type VI Affected status: not provided Allele origin: unknown	GeneReviews Accession: SCV000040944.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: PubMed (2) PubMed: 9529348‚ 20301760 BookShelf: NBK5941 BookShelf: NBK5941

Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). Canonical splice site is predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000011992). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

This sequence change affects a donor splice site in intron 14 of the PYGL gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs113993982, gnomAD 0.006%). Disruption of this splice site has been observed in individuals with glycogen storage disease type VI (PMID: 9529348, 32892177). ClinVar contains an entry for this variant (Variation ID: 11992). Studies have shown that disruption of this splice site results in 3 aberrantly spliced mRNAs and introduces a premature termination codon (PMID: 9529348). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

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
Glycogen storage disease type VI can progress to cirrhosis: ten Chinese patients with GSD VI and a literature review.	Lu SQ	Journal of pediatric endocrinology & metabolism : JPEM	2020	PMID: 32892177
Glycogen Storage Disease Type VI.	Adam MP	-	2019	PMID: 20301760
Mutations in the liver glycogen phosphorylase gene (PYGL) underlying glycogenosis type VI.	Burwinkel B	American journal of human genetics	1998	PMID: 9529348

Text-mined citations for rs113993982 ...

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 Feb 26, 2025

ClinVar Genomic variation as it relates to human health

NM_002863.5(PYGL):c.1768+1G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs113993982 ...