ClinVar Genomic variation as it relates to human health
NM_000823.4(GHRHR):c.214G>T (p.Glu72Ter)
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_000823.4(GHRHR):c.214G>T (p.Glu72Ter)
Variation ID: 15989 Accession: VCV000015989.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7p14.3 7: 30969116 (GRCh38) [ NCBI UCSC ] 7: 31008731 (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 Nov 3, 2018 Sep 16, 2024 Jul 8, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000823.4:c.214G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000814.2:p.Glu72Ter nonsense NM_000823.3:c.214G>T NC_000007.14:g.30969116G>T NC_000007.13:g.31008731G>T NG_021416.1:g.10096G>T - Protein change
- E72*
- Other names
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- Canonical SPDI
- NC_000007.14:30969115:G: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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0.00020 (T)
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Allele frequency
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The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00016
The Genome Aggregation Database (gnomAD), exomes 0.00018
1000 Genomes Project 0.00020
Exome Aggregation Consortium (ExAC) 0.00048
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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GHRHR | - | - |
GRCh38 GRCh37 |
259 | 291 |
Conditions - Germline
Condition
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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
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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 (6) |
criteria provided, multiple submitters, no conflicts
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Jul 8, 2024 | RCV000017360.40 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 9, 2022 | RCV001851885.8 |
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
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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Pathogenic
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Isolated growth hormone deficiency, type 4
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002059091.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are … (more)
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000015989, PMID:8528260, 3billion dataset).It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000175, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Abnormality of skeletal maturation (present)
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Pathogenic
(Mar 30, 2022)
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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: SCV002577236.2
First in ClinVar: Oct 08, 2022 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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: 25525159, 12788864, 9814493, 9467553, 25153028, 16355809, 8528260) (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Isolated growth hormone deficiency, type 4
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004101518.1
First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023 |
Comment:
The stop gained variant c.214G>T (p.Glu72Ter) in GHRHR gene has been previously reported in homozygous (or hemizygous) state in two siblings affected with isolated growth … (more)
The stop gained variant c.214G>T (p.Glu72Ter) in GHRHR gene has been previously reported in homozygous (or hemizygous) state in two siblings affected with isolated growth hormone deficiency. Most cases with this same mutation were found to originate from Asia, especially from India or Sri Lanka (Siklar et al. 2010). This variant has been reported to the ClinVar database as Pathogenic. Null variant (nonsense), in gene GHRHR for which loss-of-function is a known mechanism of disease. This variant is present in the gnomAD exomes database with a frequency of 0.018%. The nucleotide change in GHRHR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic (less)
Clinical Features:
Short stature (present) , Failure to thrive (present)
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Pathogenic
(Jul 08, 2024)
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criteria provided, single submitter
Method: clinical testing
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Isolated growth hormone deficiency, type 4
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005203229.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
Comment:
Variant summary: GHRHR c.214G>T (p.Glu72X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: GHRHR c.214G>T (p.Glu72X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00018 in 193754 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GHRHR causing Isolated growth hormone deficiency, type 4, allowing no conclusion about variant significance. c.214G>T has been reported in the literature in multiple biallelic individuals affected with Isolated growth hormone deficiency, type 4 (e.g. Kamijo_2004). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 15336233). ClinVar contains an entry for this variant (Variation ID: 15989). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jan 16, 2020)
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criteria provided, single submitter
Method: clinical testing
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Isolated growth hormone deficiency, type 4
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001149782.1
First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020 |
Sex: female
Tissue: blood
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Pathogenic
(Oct 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Isolated growth hormone deficiency, type 4
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV004236842.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 09, 2022)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002243817.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This premature translational stop signal has been observed in individual(s) with growth hormone deficiency (PMID: 8528260, 16355809, 25153028). In at least one individual the data … (more)
This premature translational stop signal has been observed in individual(s) with growth hormone deficiency (PMID: 8528260, 16355809, 25153028). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Indian ancestry (PMID: 12794696). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 15989). This variant is present in population databases (rs121918117, gnomAD 0.1%). This sequence change creates a premature translational stop signal (p.Glu72*) in the GHRHR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GHRHR are known to be pathogenic (PMID: 12444890, 16355809). (less)
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Pathogenic
(Jul 01, 2003)
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no assertion criteria provided
Method: literature only
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ISOLATED GROWTH HORMONE DEFICIENCY, TYPE IV
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000037632.3
First in ClinVar: Apr 04, 2013 Last updated: Nov 03, 2018 |
Comment on evidence:
In a consanguineous Indian Moslem kindred, Wajnrajch et al. (1996) demonstrated that 2 first cousins, a boy and a girl, with the typical phenotype of … (more)
In a consanguineous Indian Moslem kindred, Wajnrajch et al. (1996) demonstrated that 2 first cousins, a boy and a girl, with the typical phenotype of severe growth hormone deficiency (IGHD4; 618157), formerly IGHD1B, had a homozygous G-to-T transversion at position 265 of the GHRHR gene resulting in an amber mutation, glu72 to ter (E72X). The mutation introduced a BfaI restriction site into the amplified fragment which could be used for tracing the gene through the family. The 3.5-year-old girl and her 16-year-old cousin had shown poor growth since infancy and both were extremely short. They were prepubertal with frontal bossing and predominantly truncal obesity. Both failed to produce growth hormone in response to standard provocative tests and to repetitive stimulation with growth hormone-releasing hormone (139190). They responded to administration of growth hormone (GH; 139250). Wajnrajch et al. (1996) noted that since both growth hormone- releasing peptide, a synthetic heptapeptide, and nonpeptidyl benzamines can stimulate growth hormone release without involvement of the GHRH receptor, they might be useful in therapy of this disorder. It remained to be seen whether either class of drug could release growth hormone from a pituitary that has never been exposed to a functional GHRH signaling system. Netchine et al. (1998) investigated a Tamoulean family originating from Sri Lanka. Two brothers with extremely short stature (less than -4 SD) and no dysmorphic features were diagnosed as having complete growth hormone deficiency that was unresponsive to exogenous GHRH and was associated with prolactin levels within the lower normal range. MRI showed anterior pituitary hypoplasia with a normal pituitary stalk. Netchine et al. (1998) found the same homozygous E72X mutation that previously had been found in an Indian Moslem family by Wajnrajch et al. (1996), raising the possibility of a founder effect. There was no clear evidence for height reduction in the 3 heterozygous individuals studied. Maheshwari et al. (1998) studied 18 members of a consanguineous kindred in Sindh, Pakistan, ranging in age from newborn to 28 years. Their mean height was 7.2 SD below the norm, with mean adult heights of 130 cm for males and 113.5 cm for females. Body proportions and habitus were normal, but head circumference was 4.1 SD below the norm, and blood pressure approximately 3 SD below the norm. Serum GH did not respond to provocative stimuli. DNA sequencing revealed an E72X mutation in the extracellular domain of the GHRHR. The syndrome, which the authors termed 'dwarfism of Sindh,' is distinct from other forms of GH deficiency with respect to microcephaly, asymptomatic hypotension, and absence of features such as facial dysplasia, significant truncal obesity, microphallus, or hypoglycemia. Wajnrajch et al. (2003) studied 3 nominally unrelated kindreds segregating the E72X mutation, previously reported by Wajnrajch et al. (1996), Maheshwari et al. (1998), and Netchine et al. (1998). Haplotype analysis indicated that affected members of all 3 kindreds shared a common ancestor. The first of these kindreds came from Bombay, India; the second came from the Sindh region of Pakistan; and the third was living on the island of Delft and was of Tamil origin. The greatest similarity between haplotypes was between the Indian and the Sindh kindreds; there was less similarity between these 2 and the Delft kindred. To assess the effect of severe, congenital, isolated growth hormone deficiency on bone mass, size, and density, Maheshwari et al. (2003) performed dual energy x-ray absorptiometry (DEXA) scans in 4 adult males, previously studied by Maheshwari et al. (1998), with the E72X mutation in GHRHR. Areal bone mineral density (BMD) was low in the lumbar spine, femoral neck, forearm, and total skeleton, respectively. This low areal BMD was in part caused by the small bone size in these dwarfed patients. When corrected for size, volumetric BMD was normal to near normal. The authors concluded that GH/IGF1 deficiency has relatively little impact on bone mineralization during the bone accretion phase. This is in marked contrast to their effect on bone elongation and overall bone size. (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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A novel gross indel in the growth hormone releasing hormone receptor gene of Indian IGHD patients. | Kale S | Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society | 2014 | PMID: 25153028 |
Growth hormone releasing hormone receptor (GHRH-r) gene mutation in Indian children with familial isolated growth hormone deficiency: a study from western India. | Desai MP | Journal of pediatric endocrinology & metabolism : JPEM | 2005 | PMID: 16355809 |
A nonsense mutation (E72X) in growth hormone releasing hormone receptor (GHRHR) gene is the major cause of familial isolated growth hormone deficiency in Western region of India: founder effect suggested by analysis of dinucleotide repeat polymorphism close to GHRHR gene. | Kamijo T | Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society | 2004 | PMID: 15336233 |
Haplotype analysis of the growth hormone releasing hormone receptor locus in three apparently unrelated kindreds from the indian subcontinent with the identical mutation in the GHRH receptor. | Wajnrajch MP | American journal of medical genetics. Part A | 2003 | PMID: 12794696 |
The Impact of congenital, severe, untreated growth hormone (GH) deficiency on bone size and density in young adults: insights from genetic GH-releasing hormone receptor deficiency. | Maheshwari HG | The Journal of clinical endocrinology and metabolism | 2003 | PMID: 12788864 |
Serum GH response to pharmacological stimuli and physical exercise in two siblings with two new inactivating mutations in the GH-releasing hormone receptor gene. | Salvatori R | European journal of endocrinology | 2002 | PMID: 12444890 |
Phenotype and genetic analysis of a syndrome caused by an inactivating mutation in the growth hormone-releasing hormone receptor: Dwarfism of Sindh. | Maheshwari HG | The Journal of clinical endocrinology and metabolism | 1998 | PMID: 9814493 |
Extensive phenotypic analysis of a family with growth hormone (GH) deficiency caused by a mutation in the GH-releasing hormone receptor gene. | Netchine I | The Journal of clinical endocrinology and metabolism | 1998 | PMID: 9467553 |
Nonsense mutation in the human growth hormone-releasing hormone receptor causes growth failure analogous to the little (lit) mouse. | Wajnrajch MP | Nature genetics | 1996 | PMID: 8528260 |
Text-mined citations for rs121918117 ...
HelpRecord 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.