ClinVar Genomic variation as it relates to human health
NM_198407.2(GHSR):c.709A>T (p.Arg237Trp)
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_198407.2(GHSR):c.709A>T (p.Arg237Trp)
Variation ID: 7634 Accession: VCV000007634.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q26.31 3: 172447705 (GRCh38) [ NCBI UCSC ] 3: 172165495 (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 20, 2015 May 1, 2024 Apr 4, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_198407.2:c.709A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_940799.1:p.Arg237Trp missense NM_004122.2:c.709A>T NP_004113.1:p.Arg237Trp missense NC_000003.12:g.172447705T>A NC_000003.11:g.172165495T>A NG_021159.1:g.5752A>T Q92847:p.Arg237Trp - Protein change
- R237W
- Other names
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- Canonical SPDI
- NC_000003.12:172447704:T: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) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00010
1000 Genomes Project 30x 0.00016
Exome Aggregation Consortium (ExAC) 0.00019
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD), exomes 0.00020
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00031
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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GHSR | - | - |
GRCh38 GRCh37 |
217 | 245 |
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
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
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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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Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Apr 4, 2024 | RCV000008073.13 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 3, 2020 | RCV001266521.4 | |
Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Jan 12, 2024 | RCV001573391.8 |
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
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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
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
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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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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Short stature due to growth hormone secretagogue receptor deficiency
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000442156.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The GHSR c.709A>T (p.Arg237Trp) missense variant was identified in a compound heterozygous state in one individual with short stature and endocrine analysis consistent with partial … (more)
The GHSR c.709A>T (p.Arg237Trp) missense variant was identified in a compound heterozygous state in one individual with short stature and endocrine analysis consistent with partial isolated growth hormone deficiency (Pantel et al. 2009). Family studies revealed that the individual's unaffected mother and an unaffected sibling were heterozygous for the variant. Control data are unavailable for this variant, which is reported at a frequency of 0.00047 in the European-American population of the Exome Sequencing Project. In vitro expression experiments showed that the p.Arg237Trp variant resulted in a partial loss of constitutive activity of the receptor, though the ability to respond to ghrelin and its cell surface expression were preserved. The evidence for this variant is limited. The p.Arg237Trp variant is classified as a variant of unknown significance but suspicious for pathogenicity for partial isolated growth hormone deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Uncertain significance
(Oct 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Short stature due to growth hormone secretagogue receptor deficiency
Affected status: unknown
Allele origin:
unknown
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV001976924.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
Comment:
PM2, PP3, BP1
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Uncertain significance
(Oct 06, 2019)
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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: SCV001826122.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed with a variant on the opposite allele (in trans) in … (more)
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed with a variant on the opposite allele (in trans) in a patient with partial growth hormone deficiency and unexplained episodes of abdominal pain, vomiting, ketosis, and hypoglycemia. Unaffected parents with normal stature were heterozygous carriers (Pantel et al., 2009).; In vitro functional studies show that the R237W mutant has a lower constitutive expression compared to wild type, however, R237W demonstrated normal cell surface expression and a normal ability to bind and respond to ghrelin (Pantel et al., 2009); This variant is associated with the following publications: (PMID: 19789204) (less)
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Uncertain significance
(Jan 12, 2024)
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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: SCV002159121.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 237 of the GHSR protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 237 of the GHSR protein (p.Arg237Trp). This variant is present in population databases (rs199588904, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of growth hormone deficiency (PMID: 19789204). ClinVar contains an entry for this variant (Variation ID: 7634). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GHSR protein function. Experimental studies have shown that this missense change affects GHSR function (PMID: 19789204). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Apr 04, 2024)
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criteria provided, single submitter
Method: clinical testing
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Short stature due to growth hormone secretagogue receptor deficiency
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004809599.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
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Uncertain significance
(Feb 03, 2020)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV001444696.4
First in ClinVar: Nov 21, 2020 Last updated: May 01, 2024 |
Comment:
The alteration results in an amino acid change:_x000D_ _x000D_ The c.709A>T (p.R237W) alteration is located in coding exon 1 of the GHSR gene. This alteration … (more)
The alteration results in an amino acid change:_x000D_ _x000D_ The c.709A>T (p.R237W) alteration is located in coding exon 1 of the GHSR gene. This alteration results from a A to T substitution at nucleotide position 709, causing the arginine (R) at amino acid position 237 to be replaced by a tryptophan (W). The alteration is rare in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the c.709A>T alteration was observed in 0.0195% (55/282,042) of total alleles studied. No homozygotes were reported in gnomAD. The alteration has been observed in affected individuals:_x000D_ _x000D_ A 6 year old boy with partial isolated growth hormone deficiency (IGHD) was reported to have compound heterozygous c.709A>T (p.R237W) and c.6G>A (p.W2*) in GHSR (Pantel, 2009). The patient initially had normal birth height and weight. Growth delay (−3.0 SD) was associated with recurrent episodes of abdominal pain, vomiting, ketosis, hypoglycemia, and a low body mass index. Endocrine investigations revealed markedly low levels of IGF-I. He displayed a low growth hormone (GH) response to two provocative tests with GH peaks less than 10 ng/ml and no other pituitary hormone deficiency, consistent with the diagnosis of partial IGHD. The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.R237 amino acid is conserved in available vertebrate species. The alteration is predicted inconclusive by in silico modeling:_x000D_ _x000D_ The in silico prediction for the p.R237W alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
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Pathogenic
(Nov 01, 2009)
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no assertion criteria provided
Method: literature only
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GROWTH HORMONE DEFICIENCY, ISOLATED PARTIAL
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000028278.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 20, 2015 |
Comment on evidence:
For discussion of the arg237-to-trp (R237W) mutation in the GHSR gene that was found in compound heterozygous state in a patient with short stature and … (more)
For discussion of the arg237-to-trp (R237W) mutation in the GHSR gene that was found in compound heterozygous state in a patient with short stature and endocrine analysis consistent with isolated partial growth hormone deficiency (GHDP; 615925) by Pantel et al. (2009), see 601898.0002. (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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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001799205.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 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: SCV001964922.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 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
HelpTitle | Author | Journal | Year | Link |
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Recessive isolated growth hormone deficiency and mutations in the ghrelin receptor. | Pantel J | The Journal of clinical endocrinology and metabolism | 2009 | PMID: 19789204 |
Text-mined citations for rs199588904 ...
HelpRecord last updated May 01, 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.