ClinVar Genomic variation as it relates to human health
NM_000515.5(GH1):c.626G>A (p.Arg209His)
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_000515.5(GH1):c.626G>A (p.Arg209His)
Variation ID: 15983 Accession: VCV000015983.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q23.3 17: 63917337 (GRCh38) [ NCBI UCSC ] 17: 61994697 (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 Jan 20, 2017 May 26, 2024 Feb 3, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000515.5:c.626G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000506.2:p.Arg209His missense NM_022559.4:c.581G>A NP_072053.1:p.Arg194His missense NM_022560.4:c.506G>A NP_072054.1:p.Arg169His missense NC_000017.11:g.63917337C>T NC_000017.10:g.61994697C>T NG_011676.1:g.6502G>A NG_042788.1:g.245C>T P01241:p.Arg209His - Protein change
- R169H, R194H, R209H
- Other names
- R183H
- Canonical SPDI
- NC_000017.11:63917336: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.
The Genome Aggregation Database (gnomAD) 0.00001
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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GH-LCR | - | - | - | GRCh38 | - | 1611 |
GH1 | - | - |
GRCh38 GRCh37 |
7 | 174 |
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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Pathogenic/Likely pathogenic (3) |
no assertion criteria provided
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Feb 1, 2024 | RCV000017353.29 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 3, 2023 | RCV000992079.3 |
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
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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
(Jul 08, 2019)
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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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Athena Diagnostics
Accession: SCV001144056.1
First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2020 |
Comment:
The best available variant frequency is uninformative because there are too few occurrences in population data. Found in at least one symptomatic patient. Conflicting predictions … (more)
The best available variant frequency is uninformative because there are too few occurrences in population data. Found in at least one symptomatic patient. Conflicting predictions of the effect on the protein. Damaging to protein function(s) relevant to disease mechanism. Very strong co-segregation with disease in affected individuals from multiple families. (less)
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Pathogenic
(Feb 03, 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: SCV004297504.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 209 of the GH1 protein (p.Arg209His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 209 of the GH1 protein (p.Arg209His). This variant is present in population databases (rs137853223, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of autosomal dominant growth hormone deficiency (PMID: 17785368, 29739035, 33729509, 34006472, 34589056). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg183His. ClinVar contains an entry for this variant (Variation ID: 15983). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 01, 2007)
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no assertion criteria provided
Method: literature only
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ISOLATED GROWTH HORMONE DEFICIENCY, TYPE II
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000037625.5
First in ClinVar: Apr 04, 2013 Last updated: Jan 20, 2017 |
Comment on evidence:
In a large kindred with dominant growth hormone deficiency (IGHD2; 173100) Gertner et al. (1998) detected a heterozygous G-to-A transition at nucleotide 6664 in exon … (more)
In a large kindred with dominant growth hormone deficiency (IGHD2; 173100) Gertner et al. (1998) detected a heterozygous G-to-A transition at nucleotide 6664 in exon 5 of the GH1 gene, resulting in an arg183-to-his substitution (R183H). Hess et al. (2007) studied the phenotype-genotype correlation of subjects with IGHD2 caused by an R183H mutation in the GH1 gene in 34 affected members of 2 large families. Twenty-four of the 52 members from family 1 and 10 of the 14 from family 2 carried the same mutation in a heterozygous state. The affected subjects in family 1 were significantly shorter (-2.6 vs -0.1 standard deviation score (SDS), p less than 0.0001) and had significantly lower IGF1 (147440) serum levels (-1.9 vs -0.5 SDS, p less than 0.0001), compared with family members with a normal genotype. The affected adults exhibited great variability in their stature, ranging from -4.5 to -1.0 SD (mean -2.8 SDS), with 5 members being of normal height (greater than -2 SDS). Twelve children were diagnosed with IGHD. Two affected children had normal peak GH levels, although 1 of these subsequently demonstrated GH insufficiency. The affected children from both families exhibited large variability in their height, growth velocity, delay in bone age, age at diagnosis, peak GH response, and IGF1 levels. Hess et al. (2007) concluded that these detailed phenotypic analyses show the variable expressivity of patients bearing the R183H mutation, reflecting the spectrum of GH deficiency in affected patients, even within families, and the presence of additional genes modifying height determination. (less)
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Likely pathogenic
(May 31, 2019)
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no assertion criteria provided
Method: research
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Autosomal dominant isolated somatotropin deficiency
Affected status: yes
Allele origin:
unknown
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Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital
Accession: SCV001482369.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
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Likely pathogenic
(Feb 01, 2024)
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no assertion criteria provided
Method: clinical testing
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Autosomal dominant isolated somatotropin deficiency
Affected status: yes
Allele origin:
de novo
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Department of Pediatrics, Taizhou Central Hospital, Taizhou University Hospital
Accession: SCV005045323.1
First in ClinVar: May 26, 2024 Last updated: May 26, 2024 |
Number of individuals with the variant: 1
Ethnicity/Population group: Asia
Geographic origin: China
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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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Whole Exome Sequencing Uncovered the Genetic Architecture of Growth Hormone Deficiency Patients. | Yu C | Frontiers in endocrinology | 2021 | PMID: 34589056 |
Exome sequencing reveals genetic architecture in patients with isolated or syndromic short stature. | Fan X | Journal of genetics and genomics = Yi chuan xue bao | 2021 | PMID: 34006472 |
Comprehensive Identification of Pathogenic Gene Variants in Patients With Neuroendocrine Disorders. | Vishnopolska SA | The Journal of clinical endocrinology and metabolism | 2021 | PMID: 33729509 |
Next generation sequencing panel based on single molecule molecular inversion probes for detecting genetic variants in children with hypopituitarism. | Pérez Millán MI | Molecular genetics & genomic medicine | 2018 | PMID: 29739035 |
Isolated growth hormone deficiency due to the R183H mutation in GH1: Clinical analysis of a four-generation family. | Cabrera-Salcedo C | Clinical endocrinology | 2017 | PMID: 28626954 |
Genetic screening of a Dutch population with isolated GH deficiency (IGHD). | de Graaff LC | Clinical endocrinology | 2009 | PMID: 18785993 |
Variable phenotypes in familial isolated growth hormone deficiency caused by a G6664A mutation in the GH-1 gene. | Hess O | The Journal of clinical endocrinology and metabolism | 2007 | PMID: 17785368 |
Prolonged retention after aggregation into secretory granules of human R183H-growth hormone (GH), a mutant that causes autosomal dominant GH deficiency type II. | Zhu YL | Endocrinology | 2002 | PMID: 12399418 |
Autosomal dominant GH deficiency due to an Arg183His GH-1 gene mutation: clinical and molecular evidence of impaired regulated GH secretion. | Deladoëy J | The Journal of clinical endocrinology and metabolism | 2001 | PMID: 11502836 |
Genetic defects in the control of growth hormone secretion. | Gertner JM | Hormone research | 1998 | PMID: 9554464 |
Detection of growth hormone gene defects by dideoxy fingerprinting (ddF). | Miyata I | Endocrine journal | 1997 | PMID: 9152628 |
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Text-mined citations for rs137853223 ...
HelpRecord last updated Jun 02, 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.