ClinVar Genomic variation as it relates to human health
NM_080425.4(GNAS):c.538C>T (p.Gln180Ter)
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_080425.4(GNAS):c.538C>T (p.Gln180Ter)
Variation ID: 1048823 Accession: VCV001048823.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 20q13.32 20: 58853803 (GRCh38) [ NCBI UCSC ] 20: 57428858 (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 Apr 13, 2021 Nov 20, 2023 Jul 20, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_016592.5:c.*42+12917C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_080425.4:c.538C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_536350.2:p.Gln180Ter nonsense NM_001077490.3:c.351C>T NP_001070958.1:p.Tyr117= synonymous NM_001309861.2:c.-39+11928C>T intron variant NM_001309883.1:c.351C>T NP_001296812.1:p.Tyr117= synonymous NM_001410912.1:c.43+12917C>T intron variant NM_001410913.1:c.538C>T NP_001397842.1:p.Gln180Ter nonsense NC_000020.11:g.58853803C>T NC_000020.10:g.57428858C>T NG_016194.2:g.19064C>T NG_021433.1:g.2101G>A LRG_1051:g.2101G>A - Protein change
- Q180*
- Other names
- -
- Canonical SPDI
- NC_000020.11:58853802:C: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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00007
The Genome Aggregation Database (gnomAD) 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00010
Exome Aggregation Consortium (ExAC) 0.00011
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00041
- 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
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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GNAS | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
746 | 859 |
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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Uncertain significance (1) |
no assertion criteria provided
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- | RCV001354116.10 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV001357204.10 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV001358585.10 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV001358646.10 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV001354967.10 | |
Uncertain significance (3) |
no assertion criteria provided
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- | RCV001698589.14 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 18, 2022 | RCV002504569.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 20, 2023 | RCV003416255.4 |
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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Uncertain significance
(May 18, 2022)
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criteria provided, single submitter
Method: clinical testing
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Pseudohypoparathyroidism type I A
Progressive osseous heteroplasia McCune-Albright syndrome ACTH-independent macronodular adrenal hyperplasia 1 Pseudohypoparathyroidism type 1B Pseudohypoparathyroidism type 1C Pseudopseudohypoparathyroidism Pituitary adenoma 3, multiple types
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002815236.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Jul 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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GNAS-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004116541.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The GNAS c.538C>T variant is predicted to result in premature protein termination (p.Gln180*). In the primary transcript of the GNAS gene (NM_000516.5), this variant is … (more)
The GNAS c.538C>T variant is predicted to result in premature protein termination (p.Gln180*). In the primary transcript of the GNAS gene (NM_000516.5), this variant is located in the 5’ untranslated region (UTR) and is defined as c.-37924C>T. To our knowledge, this variant has not been reported in the literature. At PreventionGenetics, we have observed the c.538C>T variant in a patient with abnormal thyroid function and a profile that suggested resistance to thyroid hormone. This variant was inherited from the unaffected father who was apparently mosaic for the c.538C>T variant. Although truncating variants in GNAS are a known mechanism of disease, these variants are all reported in the primary transcript (NM_000516.5). The c.538C>T variant is located in exon 1 of transcript NM_080425.3 and, to our knowledge, no other protein truncating variants have been reported in this exon (Human Gene Mutation Database). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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Pseudohypoparathyroidism type 1B
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001548652.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The GNAS p.Q180* variant was identified in the literature in a cohort of 379,768 UK Biobank participants of European ancestry at a minor allele frequency … (more)
The GNAS p.Q180* variant was identified in the literature in a cohort of 379,768 UK Biobank participants of European ancestry at a minor allele frequency of 0.03063 and was classified as a benign variant for albright hereditary osteodystrophy (Wright_2019_PMID_30665703). The variant was identified in dbSNP (ID: rs200910410) but was not identified in ClinVar. The variant was identified in control databases in 28 of 267434 chromosomes at a frequency of 0.0001047, where it was observed only in the European (non-Finnish) population in 28 of 121272 chromosomes (freq: 0.0002309) (Genome Aggregation Database March 6, 2019, v2.1.1). The c.538C>T variant leads to a premature stop codon at position 180 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the GNAS gene are an established mechanism of disease in progressive osseous heteroplasia, Pseudohypoparathyroidism Ib, Pseudohypoparathyroidism Ia and is the type of variant expected to cause the disorder. However, the frequency of this loss of function variant is greater than expected for these conditions. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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Progressive osseous heteroplasia
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001549705.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The GNAS p.Q180* variant was identified in the literature in a cohort of 379,768 UK Biobank participants of European ancestry at a minor allele frequency … (more)
The GNAS p.Q180* variant was identified in the literature in a cohort of 379,768 UK Biobank participants of European ancestry at a minor allele frequency of 0.03063 and was classified as a benign variant for albright hereditary osteodystrophy (Wright_2019_PMID_30665703). The variant was identified in dbSNP (ID: rs200910410) but was not identified in ClinVar. The variant was identified in control databases in 28 of 267434 chromosomes at a frequency of 0.0001047, where it was observed only in the European (non-Finnish) population in 28 of 121272 chromosomes (freq: 0.0002309) (Genome Aggregation Database March 6, 2019, v2.1.1). The c.538C>T variant leads to a premature stop codon at position 180 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the GNAS gene are an established mechanism of disease in progressive osseous heteroplasia, Pseudohypoparathyroidism Ib, Pseudohypoparathyroidism Ia and is the type of variant expected to cause the disorder. However, the frequency of this loss of function variant is greater than expected for these conditions. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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Pseudohypoparathyroidism type 1C
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001552594.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The GNAS p.Q180* variant was identified in the literature in a cohort of 379,768 UK Biobank participants of European ancestry at a minor allele frequency … (more)
The GNAS p.Q180* variant was identified in the literature in a cohort of 379,768 UK Biobank participants of European ancestry at a minor allele frequency of 0.03063 and was classified as a benign variant for albright hereditary osteodystrophy (Wright_2019_PMID_30665703). The variant was identified in dbSNP (ID: rs200910410) but was not identified in ClinVar. The variant was identified in control databases in 28 of 267434 chromosomes at a frequency of 0.0001047, where it was observed only in the European (non-Finnish) population in 28 of 121272 chromosomes (freq: 0.0002309) (Genome Aggregation Database March 6, 2019, v2.1.1). The c.538C>T variant leads to a premature stop codon at position 180 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the GNAS gene are an established mechanism of disease in progressive osseous heteroplasia, Pseudohypoparathyroidism Ib, Pseudohypoparathyroidism Ia and is the type of variant expected to cause the disorder. However, the frequency of this loss of function variant is greater than expected for these conditions. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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Pseudopseudohypoparathyroidism
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001554366.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The GNAS p.Q180* variant was identified in the literature in a cohort of 379,768 UK Biobank participants of European ancestry at a minor allele frequency … (more)
The GNAS p.Q180* variant was identified in the literature in a cohort of 379,768 UK Biobank participants of European ancestry at a minor allele frequency of 0.03063 and was classified as a benign variant for albright hereditary osteodystrophy (Wright_2019_PMID_30665703). The variant was identified in dbSNP (ID: rs200910410) but was not identified in ClinVar. The variant was identified in control databases in 28 of 267434 chromosomes at a frequency of 0.0001047, where it was observed only in the European (non-Finnish) population in 28 of 121272 chromosomes (freq: 0.0002309) (Genome Aggregation Database March 6, 2019, v2.1.1). The c.538C>T variant leads to a premature stop codon at position 180 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the GNAS gene are an established mechanism of disease in progressive osseous heteroplasia, Pseudohypoparathyroidism Ib, Pseudohypoparathyroidism Ia and is the type of variant expected to cause the disorder. However, the frequency of this loss of function variant is greater than expected for these conditions. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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Pseudohypoparathyroidism type I A
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001554440.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The GNAS p.Q180* variant was identified in the literature in a cohort of 379,768 UK Biobank participants of European ancestry at a minor allele frequency … (more)
The GNAS p.Q180* variant was identified in the literature in a cohort of 379,768 UK Biobank participants of European ancestry at a minor allele frequency of 0.03063 and was classified as a benign variant for albright hereditary osteodystrophy (Wright_2019_PMID_30665703). The variant was identified in dbSNP (ID: rs200910410) but was not identified in ClinVar. The variant was identified in control databases in 28 of 267434 chromosomes at a frequency of 0.0001047, where it was observed only in the European (non-Finnish) population in 28 of 121272 chromosomes (freq: 0.0002309) (Genome Aggregation Database March 6, 2019, v2.1.1). The c.538C>T variant leads to a premature stop codon at position 180 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the GNAS gene are an established mechanism of disease in progressive osseous heteroplasia, Pseudohypoparathyroidism Ib, Pseudohypoparathyroidism Ia and is the type of variant expected to cause the disorder. However, the frequency of this loss of function variant is greater than expected for these conditions. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001917030.1 First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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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: SCV001951138.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001971780.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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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
HelpThere are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs200910410 ...
HelpRecord last updated Apr 20, 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.