ClinVar Genomic variation as it relates to human health
NM_000516.7(GNAS):c.772C>T (p.Arg258Trp)
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.
Pathogenic(7); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000516.7(GNAS):c.772C>T (p.Arg258Trp)
Variation ID: 15941 Accession: VCV000015941.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 20q13.32 20: 58909737 (GRCh38) [ NCBI UCSC ] 20: 57484792 (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 Aug 22, 2016 Apr 15, 2024 Oct 1, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000516.7:c.772C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000507.1:p.Arg258Trp missense NM_016592.5:c.*678C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
3 prime UTR NM_080425.4:c.2701C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_536350.2:p.Arg901Trp missense NM_001077488.5:c.775C>T NP_001070956.1:p.Arg259Trp missense NM_001077489.4:c.727C>T NP_001070957.1:p.Arg243Trp missense NM_001077490.3:c.*633C>T 3 prime UTR NM_001309840.2:c.595C>T NP_001296769.1:p.Arg199Trp missense NM_001309861.2:c.595C>T NP_001296790.1:p.Arg199Trp missense NM_080426.4:c.730C>T NP_536351.1:p.Arg244Trp missense NC_000020.11:g.58909737C>T NC_000020.10:g.57484792C>T NG_016194.2:g.74998C>T - Protein change
- R258W, R243W, R244W, R259W, R901W, R199W
- Other names
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- Canonical SPDI
- NC_000020.11:58909736: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
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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, single submitter
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Jan 6, 2017 | RCV000017306.25 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Oct 1, 2023 | RCV000595336.13 | |
Pathogenic (1) |
criteria provided, single submitter
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May 17, 2018 | RCV001265731.2 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 1, 2022 | RCV001731308.2 |
Submissions - Germline
Classification
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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
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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
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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
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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
(Jan 06, 2017)
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criteria provided, single submitter
Method: clinical testing
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Pseudopseudohypoparathyroidism
Affected status: yes
Allele origin:
de novo
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Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris
Accession: SCV000586752.1
First in ClinVar: Aug 22, 2016 Last updated: Aug 22, 2016 |
Comment:
Intellectual disability; small stature
Number of individuals with the variant: 1
Age: 10-19 years
Sex: male
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Uncertain significance
(Nov 09, 2016)
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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: SCV000702092.2
First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018 |
Number of individuals with the variant: 3
Sex: mixed
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Pathogenic
(Jul 02, 2021)
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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: SCV002007492.2
First in ClinVar: Nov 06, 2021 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect as R258W causes a specific defect in activation (Warner et al., 1998); Not observed in large population cohorts … (more)
Published functional studies demonstrate a damaging effect as R258W causes a specific defect in activation (Warner et al., 1998); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 9727013, 31886927, 27535533, 28708303) (less)
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Pathogenic
(Oct 01, 2023)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004150724.4
First in ClinVar: Nov 20, 2023 Last updated: Apr 15, 2024 |
Comment:
GNAS: PM2, PM5, PS4:Moderate, PM6:Supporting, PP2, PP3, PS3:Supporting
Number of individuals with the variant: 1
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Pathogenic
(Jun 01, 2020)
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criteria provided, single submitter
Method: research
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Pseudohypoparathyroidism type I A
Affected status: yes
Allele origin:
de novo
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Genetics of Obesity Study, University of Cambridge
Accession: SCV001573818.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
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Pathogenic
(Sep 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Pseudohypoparathyroidism type I A
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002572522.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.69; 3Cnet: 0.54). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000015941). A different missense change at the same codon (p.Arg258Gln) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000453009). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Abnormal aortic morphology (present) , Aortic valve stenosis (present) , Aortic regurgitation (present) , Global developmental delay (present) , Delayed speech and language development (present) … (more)
Abnormal aortic morphology (present) , Aortic valve stenosis (present) , Aortic regurgitation (present) , Global developmental delay (present) , Delayed speech and language development (present) , Enuresis (present) , Obesity (present) , Abnormal circulating lipid concentration (present) , Macrocephaly (present) , Insulin resistance (present) , Hypertensive disorder (present) , Pes planus (present) , Joint laxity (present) (less)
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Pathogenic
(May 17, 2018)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV001443900.2
First in ClinVar: Nov 21, 2020 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Prominent nasal tip (present) , Delayed puberty (present) , Hypothyroidism (present) , Kyphosis (present) , Smooth philtrum (present) , Autistic disorder of childhood onset (present) … (more)
Prominent nasal tip (present) , Delayed puberty (present) , Hypothyroidism (present) , Kyphosis (present) , Smooth philtrum (present) , Autistic disorder of childhood onset (present) , Macrocephalus (present) , Prominent forehead (present) , Scoliosis (present) , Abnormality of the skeletal system (present) , Intellectual disability (present) , Broad thumb (present) , Hypohidrosis (present) , Abnormality of the dentition (present) , Behavioral abnormality (present) , Global developmental delay (present) , Developmental regression (present) (less)
Sex: male
Ethnicity/Population group: Caucasian
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Pathogenic
(Sep 17, 2023)
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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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Invitae
Accession: SCV004298111.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This variant is also known as c.775C>T (p.Arg259Trp). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly … (more)
This variant is also known as c.775C>T (p.Arg259Trp). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 258 of the GNAS protein (p.Arg258Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of GNAS-related conditions (PMID: 28708303, 31886927, 34614324). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 15941). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GNAS protein function. Experimental studies have shown that this missense change affects GNAS function (PMID: 9727013, 34614324). This variant disrupts the p.Arg258 amino acid residue in GNAS. Other variant(s) that disrupt this residue have been observed in individuals with GNAS-related conditions (PMID: 29095814, 34614324), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 11, 1998)
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no assertion criteria provided
Method: literature only
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PSEUDOPSEUDOHYPOPARATHYROIDISM
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000037578.2
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
In a 24-year-old man with PPHP (612463), Warner et al. (1998) identified a de novo arg258-to-trp (R258W) mutation in the GNAS1 gene. Arg258 is a … (more)
In a 24-year-old man with PPHP (612463), Warner et al. (1998) identified a de novo arg258-to-trp (R258W) mutation in the GNAS1 gene. Arg258 is a nonconserved residue adjacent to a highly conserved glutamic acid residue, glu259, that is important for contact between switch 2 and 3 in the activated state. Warner et al. (1998) presented evidence that substitution of arg258 led to defective GDP binding, resulting in increased thermolability and decreased activation. Developmental delay, brachycephaly, and decreased muscle tone were noted by age 10 months. Throughout childhood he was small for his age and stocky in appearance. By 6 years, he developed learning disabilities as well as impulsive and aggressive behavior. Brachydactyly involved the distal phalanx of the thumb and the fourth metacarpals bilaterally. He also had intracranial calcifications in the globus pallidus. There was no evidence of resistance to parathyroid hormone or thyrotropin. (less)
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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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Obesity-Associated GNAS Mutations and the Melanocortin Pathway. | Mendes de Oliveira E | The New England journal of medicine | 2021 | PMID: 34614324 |
Maternal Transmission Ratio Distortion of GNAS Loss-of-Function Mutations. | Snanoudj S | Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research | 2020 | PMID: 31886927 |
Proband-only medical exome sequencing as a cost-effective first-tier genetic diagnostic test for patients without prior molecular tests and clinical diagnosis in a developing country: the China experience. | Hu X | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29095814 |
Using medical exome sequencing to identify the causes of neurodevelopmental disorders: Experience of 2 clinical units and 216 patients. | Chérot E | Clinical genetics | 2018 | PMID: 28708303 |
A novel mutation in the switch 3 region of Gsalpha in a patient with Albright hereditary osteodystrophy impairs GDP binding and receptor activation. | Warner DR | The Journal of biological chemistry | 1998 | PMID: 9727013 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GNAS | - | - | - | - |
Text-mined citations for rs137854535 ...
HelpRecord last updated Apr 15, 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.