ClinVar Genomic variation as it relates to human health
NM_054021.2(GPR101):c.924G>C (p.Glu308Asp)
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.
Uncertain significance(1); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_054021.2(GPR101):c.924G>C (p.Glu308Asp)
Variation ID: 167871 Accession: VCV000167871.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq26.3 X: 137030751 (GRCh38) [ NCBI UCSC ] X: 136112910 (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 9, 2018 Mar 16, 2024 Dec 22, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_054021.2:c.924G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_473362.1:p.Glu308Asp missense NC_000023.11:g.137030751C>G NC_000023.10:g.136112910C>G NG_016367.2:g.8245G>C LRG_1000:g.8245G>C LRG_1000t1:c.924G>C LRG_1000p1:p.Glu308Asp Q96P66:p.Glu308Asp - Protein change
- E308D
- Other names
- GPR101, GLU308ASP (rs73637412)
- Canonical SPDI
- NC_000023.11:137030750:C:G
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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.
1000 Genomes Project 30x 0.00062
Trans-Omics for Precision Medicine (TOPMed) 0.00362
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
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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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GPR101 | - | - |
GRCh38 GRCh37 |
44 | 217 |
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
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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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Uncertain significance (3) |
criteria provided, single submitter
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May 28, 2019 | RCV000154187.13 | |
Likely benign (3) |
criteria provided, single submitter
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Dec 22, 2023 | RCV000887712.8 | |
Likely benign (1) |
criteria provided, single submitter
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Mar 3, 2020 | RCV003927490.1 |
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 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Pituitary adenoma, growth hormone-secreting, 2
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001142026.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Likely benign
(Dec 22, 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: SCV001031287.4
First in ClinVar: Dec 17, 2019 Last updated: Feb 14, 2024 |
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Likely benign
(Mar 03, 2020)
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criteria provided, single submitter
Method: clinical testing
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GPR101-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004738771.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Likely benign
(-)
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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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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001798856.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
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Pathogenic
(Mar 26, 2015)
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no assertion criteria provided
Method: literature only
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PITUITARY ADENOMA 2, GROWTH HORMONE-SECRETING
Affected status: not provided
Allele origin:
unknown
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OMIM
Accession: SCV000203835.8
First in ClinVar: Feb 02, 2015 Last updated: Jul 07, 2022 |
Comment on evidence:
In 11 of 248 patients with acromegaly and growth hormone-producing adenomas (PITA2; 300943), Trivellin et al. (2014) identified a c.924G-C transversion in the GPR101 gene, … (more)
In 11 of 248 patients with acromegaly and growth hormone-producing adenomas (PITA2; 300943), Trivellin et al. (2014) identified a c.924G-C transversion in the GPR101 gene, resulting in a glu308-to-asp (E308D) substitution. In 3 mutation carriers, the mutation appeared to be a germline event, as the mutation was detected in peripheral blood. In 8 patients, the mutation was only seen in tumor DNA, and in 1 patient, it was confirmed as a de novo somatic mutation, as it was not found in peripheral blood. This mutation was not found in 7,600 control samples from public databases. Transfection of a construct expressing GPR101 containing the E308D mutation increased proliferation and growth hormone secretion in a rat pituitary cell line. Roohi (2015) reported that the E308D mutation in GPR101 shows an allele frequency of 0.55% among Europeans in the ExAC database and 0.36% among the total cohort of 61,500 unrelated individuals. Given the frequency of the variant, Roohi (2015) urged caution in interpreting it as a disease-associated variant. Daly et al. (2015) responded that the SNP rs73637412 describes both E308D (c.924G-C) and its synonymous counterpart, c.924G-A. The synonymous variant is reported at a lower frequency in the ExAC database than in other databases, suggesting discrepancies in variant calling. Daly et al. (2015) pointed out that the presence of the E308D variant in pituitary tumors, as well as constitutively, supports a gain of function. Iacovazzo et al. (2016) sequenced DNA from 579 acromegaly patients and identified 4 patients with a germline E308D mutation in the GPR101 gene, none of whom had a family history of pituitary adenoma. The authors noted that the allele frequency of the E308D variant in this series, 0.45%, was similar to that reported in the ExAC database (0.37%). (less)
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Likely benign
(-)
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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: SCV001964749.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Pituitary adenoma, growth hormone-secreting, 2
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000731205.2
First in ClinVar: Apr 09, 2018 Last updated: Oct 01, 2022 |
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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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Genetic and clinical characteristics of Japanese patients with sporadic somatotropinoma. | Matsumoto R | Endocrine journal | 2016 | PMID: 27498687 |
Copy number variation analysis detects novel candidate genes involved in follicular growth and oocyte maturation in a cohort of premature ovarian failure cases. | Tšuiko O | Human reproduction (Oxford, England) | 2016 | PMID: 27301361 |
Germline or somatic GPR101 duplication leads to X-linked acrogigantism: a clinico-pathological and genetic study. | Iacovazzo D | Acta neuropathologica communications | 2016 | PMID: 27245663 |
Analysis of GPR101 and AIP genes mutations in acromegaly: a multicentric study. | Ferraù F | Endocrine | 2016 | PMID: 26815903 |
Very low frequency of germline GPR101 genetic variation and no biallelic defects with AIP in a large cohort of patients with sporadic pituitary adenomas. | Lecoq AL | European journal of endocrinology | 2016 | PMID: 26792934 |
Gigantism, acromegaly, and GPR101 mutations. | Roohi J | The New England journal of medicine | 2015 | PMID: 25806921 |
Gigantism, acromegaly, and GPR101 mutations. | Daly AF | The New England journal of medicine | 2015 | PMID: 25806919 |
Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. | Trivellin G | The New England journal of medicine | 2014 | PMID: 25470569 |
Text-mined citations for rs73637412 ...
HelpRecord last updated Mar 17, 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.