Reported in the heterozgyous state in a patient with severe growth retardation and growth hormone insensitivity without typical craniofacial or somatic features of Laron syndrome, and RNA studies in patient fibroblasts suggested that mutant transcripts are subject to nonsense-mediated decay (Gorbenko del Blanco et al., 2012); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 16932322, 25525159, 8504296, 8488849, 25411237, 22117696, 28743110)
ClinVar Genomic variation as it relates to human health
NM_000163.5(GHR):c.703C>T (p.Arg235Ter)
Germline
Classification
Help
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.
(6)
Help
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
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000163.5(GHR):c.703C>T (p.Arg235Ter)
Variation ID: 8639 Accession: VCV000008639.6
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5p12 5: 42711291 (GRCh38) [ NCBI UCSC ] 5: 42711393 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Feb 15, 2015 Aug 25, 2024 Jan 16, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000163.5:c.703C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000154.1:p.Arg235Ter nonsense NM_001242399.2:c.724C>T NP_001229328.1:p.Arg242Ter nonsense NM_001242400.2:c.703C>T NP_001229329.1:p.Arg235Ter nonsense NM_001242401.4:c.703C>T NP_001229330.1:p.Arg235Ter nonsense NM_001242402.2:c.703C>T NP_001229331.1:p.Arg235Ter nonsense NM_001242403.3:c.703C>T NP_001229332.1:p.Arg235Ter nonsense NM_001242404.2:c.703C>T NP_001229333.1:p.Arg235Ter nonsense NM_001242405.2:c.703C>T NP_001229334.1:p.Arg235Ter nonsense NM_001242406.2:c.703C>T NP_001229335.1:p.Arg235Ter nonsense NM_001242460.2:c.637C>T NP_001229389.1:p.Arg213Ter nonsense NM_001242462.1:c.703C>T NP_001229391.1:p.Arg235Ter nonsense NC_000005.10:g.42711291C>T NC_000005.9:g.42711393C>T NG_011688.2:g.292368C>T - Protein change
- R235*, R213*, R242*
- Other names
-
R217*
p.Arg235Ter
- Canonical SPDI
- NC_000005.10:42711290:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
The Genome Aggregation Database (gnomAD) 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00008
- 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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| GHR | - | - |
GRCh38 GRCh37 |
482 | 525 | |
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. |
|---|---|---|---|---|
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jan 2, 2020 | RCV000009171.8 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 16, 2024 | RCV000760385.5 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jul 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000890250.2
First in ClinVar: Mar 19, 2019 Last updated: Jul 29, 2023 |
Comment:
Reported in the heterozgyous state in a patient with severe growth retardation and growth hormone insensitivity without typical craniofacial or somatic features of Laron syndrome, … (more)
Reported in the heterozgyous state in a patient with severe growth retardation and growth hormone insensitivity without typical craniofacial or somatic features of Laron syndrome, and RNA studies in patient fibroblasts suggested that mutant transcripts are subject to nonsense-mediated decay (Gorbenko del Blanco et al., 2012); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 16932322, 25525159, 8504296, 8488849, 25411237, 22117696, 28743110) (less)
|
|
|
Pathogenic
(Jan 16, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003525658.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg235*) in the GHR gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg235*) in the GHR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GHR are known to be pathogenic (PMID: 1999489, 8488849). This variant is present in population databases (rs121909363, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Laron syndrome (PMID: 8504296). This variant is also known as R217W. ClinVar contains an entry for this variant (Variation ID: 8639). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Jan 02, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Laron-type isolated somatotropin defect
Affected status: yes
Allele origin:
germline
|
Breakthrough Genomics, Breakthrough Genomics
Accession: SCV005088804.2
First in ClinVar: Aug 04, 2024 Last updated: Aug 25, 2024 |
Comment:
This variant is predicted to cause premature termination of the protein (p.Arg235Ter). The truncated protein is likely to lack the transmembrane domain and cytoplasmic domain … (more)
This variant is predicted to cause premature termination of the protein (p.Arg235Ter). The truncated protein is likely to lack the transmembrane domain and cytoplasmic domain of the protein [UniProt]; this will likely result in loss-of-function. The variant has been previously reported in individuals affected with Laron syndrome [PMID: 8488849, 17598975]. (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Laron-type isolated somatotropin defect
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004048443.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The c.724C>T (p.Arg242Ter) variant in the GHR gene has been reported previously in the homozygous state in individuals with a clinical and biochemical phenotype consistent … (more)
The c.724C>T (p.Arg242Ter) variant in the GHR gene has been reported previously in the homozygous state in individuals with a clinical and biochemical phenotype consistent with Laron syndrome (Amselem et al., 1993; Berg et al., 1993; Storr et al., 2015). The stop gained variant in GHR gene has been reported to the ClinVar database as Pathogenic. The variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.002% in the gnomAD exomes database. This variant has been shown to cause loss of normal protein function through nonsense-mediated mRNA decay (Gorbenko del Blanco et al., 2012). The nucleotide change in GHR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Failure to thrive (present) , Joint laxity (present) , Motor delay (present)
|
|
|
Pathogenic
(May 01, 1993)
|
no assertion criteria provided
Method: literature only
|
LARON SYNDROME
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000029388.2
First in ClinVar: Apr 04, 2013 Last updated: Feb 15, 2015 |
Comment on evidence:
Berg et al. (1993) found a homozygous R217X mutation in the GHR gene in an African American patient with Laron syndrome (262500).
|
|
|
Pathogenic
(Aug 07, 2013)
|
no assertion criteria provided
Method: clinical testing
|
Laron-type isolated somatotropin defect
Affected status: yes
Allele origin:
germline
|
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000692134.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
|
Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Arg235*) in the GHR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GHR are known to be pathogenic (PMID: 1999489, 8488849). This variant is present in population databases (rs121909363, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Laron syndrome (PMID: 8504296). This variant is also known as R217W. ClinVar contains an entry for this variant (Variation ID: 8639). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant is predicted to cause premature termination of the protein (p.Arg235Ter). The truncated protein is likely to lack the transmembrane domain and cytoplasmic domain of the protein [UniProt]; this will likely result in loss-of-function. The variant has been previously reported in individuals affected with Laron syndrome [PMID: 8488849, 17598975].
Comment:
The c.724C>T (p.Arg242Ter) variant in the GHR gene has been reported previously in the homozygous state in individuals with a clinical and biochemical phenotype consistent with Laron syndrome (Amselem et al., 1993; Berg et al., 1993; Storr et al., 2015). The stop gained variant in GHR gene has been reported to the ClinVar database as Pathogenic. The variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.002% in the gnomAD exomes database. This variant has been shown to cause loss of normal protein function through nonsense-mediated mRNA decay (Gorbenko del Blanco et al., 2012). The nucleotide change in GHR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
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. |
Comment:
Reported in the heterozgyous state in a patient with severe growth retardation and growth hormone insensitivity without typical craniofacial or somatic features of Laron syndrome, and RNA studies in patient fibroblasts suggested that mutant transcripts are subject to nonsense-mediated decay (Gorbenko del Blanco et al., 2012); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 16932322, 25525159, 8504296, 8488849, 25411237, 22117696, 28743110)
Comment:
This sequence change creates a premature translational stop signal (p.Arg235*) in the GHR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GHR are known to be pathogenic (PMID: 1999489, 8488849). This variant is present in population databases (rs121909363, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Laron syndrome (PMID: 8504296). This variant is also known as R217W. ClinVar contains an entry for this variant (Variation ID: 8639). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant is predicted to cause premature termination of the protein (p.Arg235Ter). The truncated protein is likely to lack the transmembrane domain and cytoplasmic domain of the protein [UniProt]; this will likely result in loss-of-function. The variant has been previously reported in individuals affected with Laron syndrome [PMID: 8488849, 17598975].
Comment:
The c.724C>T (p.Arg242Ter) variant in the GHR gene has been reported previously in the homozygous state in individuals with a clinical and biochemical phenotype consistent with Laron syndrome (Amselem et al., 1993; Berg et al., 1993; Storr et al., 2015). The stop gained variant in GHR gene has been reported to the ClinVar database as Pathogenic. The variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.002% in the gnomAD exomes database. This variant has been shown to cause loss of normal protein function through nonsense-mediated mRNA decay (Gorbenko del Blanco et al., 2012). The nucleotide change in GHR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Spectrum of growth hormone receptor mutations and associated haplotypes in Laron syndrome. | Amselem S | Human molecular genetics | 1993 | PMID: 8504296 |
| Diverse growth hormone receptor gene mutations in Laron syndrome. | Berg MA | American journal of human genetics | 1993 | PMID: 8488849 |
| Recurrent nonsense mutations in the growth hormone receptor from patients with Laron dwarfism. | Amselem S | The Journal of clinical investigation | 1991 | PMID: 1999489 |
Text-mined citations for rs121909363 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.