ClinVar Genomic variation as it relates to human health
NM_021957.4(GYS2):c.547C>T (p.Gln183Ter)
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_021957.4(GYS2):c.547C>T (p.Gln183Ter)
Variation ID: 214529 Accession: VCV000214529.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12p12.1 12: 21574275 (GRCh38) [ NCBI UCSC ] 12: 21727209 (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 Oct 11, 2015 Feb 4, 2024 Feb 23, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_021957.4:c.547C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_068776.2:p.Gln183Ter nonsense NC_000012.12:g.21574275G>A NC_000012.11:g.21727209G>A NG_016167.1:g.35573C>T LRG_1293:g.35573C>T LRG_1293t1:c.547C>T LRG_1293p1:p.Gln183Ter - Protein change
- Q183*
- Other names
- p.Q183*:CAG>TAG
- NM_021957.4(GYS2):c.547C>T
- p.Gln183Ter
- Canonical SPDI
- NC_000012.12:21574274:G:A
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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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0.00020 (A)
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00004
The Genome Aggregation Database (gnomAD) 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00005
Exome Aggregation Consortium (ExAC) 0.00008
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
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
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. |
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GYS2 | - | - |
GRCh38 GRCh37 |
260 | 327 |
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. |
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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 23, 2018 | RCV000199810.4 | |
Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Feb 23, 2023 | RCV000763306.12 |
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. |
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Pathogenic
(Apr 23, 2018)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000860991.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disorder due to hepatic glycogen synthase deficiency
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893973.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Jul 16, 2014)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000251594.11
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Comment:
p.Gln183Stop (CAG>TAG): c.547 C>T in exon 4 of the GYS2 gene (NM_021957.3). The Q183X nonsense mutation in the GYS2 gene has been reported in association … (more)
p.Gln183Stop (CAG>TAG): c.547 C>T in exon 4 of the GYS2 gene (NM_021957.3). The Q183X nonsense mutation in the GYS2 gene has been reported in association with glycogen storage disease, type 0. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is found in MITONUC-MITOP panel(s). (less)
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Pathogenic
(Mar 31, 2022)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disorder due to hepatic glycogen synthase deficiency
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002766882.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0102 - Loss of function is a known … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with liver glycogen storage disease 0 (MIM#240600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are reported to have variable clinical phenotypes (PMIDs: 32395408, 28245189, 18341095). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (13 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in patients with glycogen storage disease type 0 (ClinVar, PMIDs: 12072888, 32377253). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity and has previously been reported in patients with glycogen storage disease 0 (ClinVar, PMID: 32395408). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant in a recessive disease. (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Aug 26, 2021)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disorder due to hepatic glycogen synthase deficiency
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001379253.3
First in ClinVar: Jul 16, 2020 Last updated: Feb 07, 2023 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln183*) in the GYS2 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Gln183*) in the GYS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GYS2 are known to be pathogenic (PMID: 9691087). This variant is present in population databases (rs201157731, ExAC 0.02%). This premature translational stop signal has been observed in individual(s) with glycogen storage disease type 0 (PMID: 12072888). ClinVar contains an entry for this variant (Variation ID: 214529). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 25, 2023)
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criteria provided, single submitter
Method: curation
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Glycogen storage disorder due to hepatic glycogen synthase deficiency
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV003761320.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The heterozygous p.Gln183Ter variant in GYS2 was identified by our study in one individual with hypotonia. The p.Gln183Ter variant in GYS2 has been previously reported … (more)
The heterozygous p.Gln183Ter variant in GYS2 was identified by our study in one individual with hypotonia. The p.Gln183Ter variant in GYS2 has been previously reported in two unrelated individuals with liver glycogen storage disorder 0 but has been identified in 0.01% (9/68028) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs201157731). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. These two affected individuals (PMID: 12072888, PMID: 32377253) were compound heterozygous who carried pathogenic or likely pathogenic variants in trans (PMID: 12072888, PMID: 32377253, ClinVar Variation ID: 937499), which increases the likelihood that the p.Gln183Ter variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 214529) and has been interpreted as pathogenic by multiple submitters. This nonsense variant leads to a premature termination codon at position 183, which is predicted to lead to a truncated or absent protein. Loss of function of the GYS2 gene is strongly associated to autosomal recessive liver glycogen storage disorder 0. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive liver glycogen storage disorder 0. ACMG/AMP Criteria applied: PVS1_Strong, PM3_Strong (Richards 2015). (less)
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Pathogenic
(Dec 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disorder due to hepatic glycogen synthase deficiency
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001520627.2
First in ClinVar: Mar 22, 2021 Last updated: Mar 11, 2023 |
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Pathogenic
(Feb 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disorder due to hepatic glycogen synthase deficiency
Affected status: yes
Allele origin:
unknown
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3billion
Accession: SCV003841517.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). This homozygous variant was predicted to result … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). This homozygous variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic 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: VCV000214529 / PMID: 12072888). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Hepatic steatosis (present) , Hepatomegaly (present) , Hepatic steatosis (present)
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Pathogenic
(Jun 29, 2020)
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criteria provided, single submitter
Method: clinical testing
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Glycogen storage disorder due to hepatic glycogen synthase deficiency
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002024937.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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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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Hepatic glycogen synthase (GYS2) deficiency: seven novel patients and seven novel variants. | Kamenets EA | JIMD reports | 2020 | PMID: 32395408 |
PERSISTENT ASYMPTOMATIC SEVERE HYPOGLYCAEMIA DUE TO TYPE 0A GLYCOGENOSIS - GENERAL AND ORO-DENTAL ASPECTS. | Matei L | Acta endocrinologica (Bucharest, Romania : 2005) | 2019 | PMID: 32377253 |
The variable clinical phenotype of three patients with hepatic glycogen synthase deficiency. | Kasapkara ÇS | Journal of pediatric endocrinology & metabolism : JPEM | 2017 | PMID: 28245189 |
The variable clinical phenotype of liver glycogen synthase deficiency. | Spiegel R | Journal of pediatric endocrinology & metabolism : JPEM | 2007 | PMID: 18341095 |
Glycogen synthase deficiency (glycogen storage disease type 0) presenting with hyperglycemia and glucosuria: report of three new mutations. | Bachrach BE | The Journal of pediatrics | 2002 | PMID: 12072888 |
Mutations in the liver glycogen synthase gene in children with hypoglycemia due to glycogen storage disease type 0. | Orho M | The Journal of clinical investigation | 1998 | PMID: 9691087 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GYS2 | - | - | - | - |
Text-mined citations for rs201157731 ...
HelpRecord last updated Mar 30, 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.