VCV000015971.3 - ClinVar

NM_000515.5(GH1):c.291+1G>C

Germline

Classification

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.

(3)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000515.5(GH1):c.291+1G>C

Variation ID: 15971 Accession: VCV000015971.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q23.3 17: 63918016 (GRCh38) [ NCBI UCSC ] 17: 61995376 (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	Apr 4, 2013	Mar 18, 2023	Feb 23, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000515.5:c.291+1G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_022559.4:c.246+1G>C		splice donor
NM_022560.4:c.172-92G>C		intron variant
NC_000017.11:g.63918016C>G
NC_000017.10:g.61995376C>G
NG_011676.1:g.5823G>C
NG_042788.1:g.924C>G

... more HGVS ... less HGVS

Protein change

Other names

IVS3, G-C, +1

Canonical SPDI

NC_000017.11:63918015:C:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Links

OMIM: 139250.0010 dbSNP: rs71640277 ClinGen: CA213429 VarSome

Comment on variant

NCBI staff reviewed the sequence information reported in PubMed 7714096 Fig. 5 to determine the location of this allele on the current reference sequence.

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
Gene	OMIM	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.
GH-LCR	-	-	-	GRCh38	-	1630
GH1		-	-	GRCh38 GRCh37	7	179

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.
Autosomal dominant isolated somatotropin deficiency	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Feb 23, 2023	RCV000017341.29

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 (Aug 18, 2011)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: curation, clinical testing	Idiopathic Growth Hormone Deficiency Type II (autosomal dominant) Affected status: unknown, yes Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000052590.2 First in ClinVar: Apr 04, 2013 Last updated: Apr 07, 2022	Publications: PubMed (22) PubMed: 9432120‚ 8923859‚ 9799079‚ 10549303‚ 18785993‚ 8530604‚ 17360215‚ 10469016‚ 10629163‚ 11914025‚ 12574219‚ 9578959‚ 11502827‚ 17178704‚ 9152628‚ 11836331‚ 12510984‚ 17336732‚ 10698162‚ 15671105‚ 12399418‚ 7714096 Comment: Converted during submission to Pathogenic. Observation 1: Number of individuals with the variant: 1 Observation 2: Number of individuals with the variant: 3 Observation 3: Number of individuals with the variant: 2 Observation 4: Tissue: Blood
Pathogenic (Feb 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal dominant isolated somatotropin deficiency Affected status: yes Allele origin: unknown	3billion Accession: SCV003841529.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Comment: The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to alter splicing and result in a loss or disruption of … (more) The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000015971). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Decreased response to growth hormone stimulation test (present)
Pathogenic (Nov 01, 1996)	no assertion criteria provided Method: literature only	ISOLATED GROWTH HORMONE DEFICIENCY, TYPE II Affected status: not provided Allele origin: germline	OMIM Accession: SCV000037613.4 First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016	Publications: PubMed (3) PubMed: 7714096‚ 8923859‚ 8530604 Comment on evidence: Binder and Ranke (1995) reported a G-to-C transversion of the first base of the donor splice site of intron 3 (IVS3+1G-C) in the GH1 gene … (more) Binder and Ranke (1995) reported a G-to-C transversion of the first base of the donor splice site of intron 3 (IVS3+1G-C) in the GH1 gene in a sporadic case of isolated growth hormone deficiency type II (IGHD2; 173100) in a German patient. This mutation was dominant negative and arose de novo. They also reported RT-PCR data suggesting overexpression of the mutant GH1 allele and speculated that the dominant-negative effect might occur because of this imbalance in expression of the mutant and normal alleles. However, Binder et al. (1996) found equal quantities of transcripts in studies using an RNA protection assay to determine the relative expression of the intron 3 +1 G-to-C mutant and normal GH1 alleles. In normal pituitary, they found 3 GH1 mRNA species with the variant lacking exon 3, which comprised approximately 5% of the total GH1 mRNA. In contrast, lymphoblasts from the proband, who was heterozygous for the transition at intron 1, contained equal amounts of mRNA with or without exon 3. Furthermore, secreted GH1, measured by enzyme-linked immunosorbent assay, was present in equal concentrations in media from normal and mutant cells. Thus, GH1 mRNA lacking exon 3 was expressed in proportion to the dosage of the mutant gene, and dominant-negative effects on GH1 secretion were not seen in lymphoblasts. Their findings are compatible with a dominant-negative mechanism involving interaction between normal and mutant proteins in secretory vesicles of somatotropes, as suggested by Cogan et al. (1995). (less)

Comment:

The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000015971). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genetic screening of a Dutch population with isolated GH deficiency (IGHD).	de Graaff LC	Clinical endocrinology	2009	PMID: 18785993
Catch-up growth in autosomal dominant isolated growth hormone deficiency (IGHD type II).	Binder G	Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society	2007	PMID: 17360215
Genetics of growth hormone deficiency.	Mullis PE	Endocrinology and metabolism clinics of North America	2007	PMID: 17336732
A novel splicing mutation in exon 4 (456G>A) of the GH1 gene in a patient with congenital isolated growth hormone deficiency.	Fofanova OV	Hormones (Athens, Greece)	2006	PMID: 17178704
Isolated autosomal dominant growth hormone deficiency: an evolving pituitary deficit? A multicenter follow-up study.	Mullis PE	The Journal of clinical endocrinology and metabolism	2005	PMID: 15671105
A novel IVS2 -2A>T splicing mutation in the GH-1 gene in familial isolated growth hormone deficiency type II in the spectrum of other splicing mutations in the Russian population.	Fofanova OV	The Journal of clinical endocrinology and metabolism	2003	PMID: 12574219
New GH-1 gene mutations: expanding the spectrum of causes of isolated growth hormone deficiency.	Mullis PE	Journal of pediatric endocrinology & metabolism : JPEM	2002	PMID: 12510984
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
An exon splice enhancer mutation causes autosomal dominant GH deficiency.	Moseley CT	The Journal of clinical endocrinology and metabolism	2002	PMID: 11836331
A novel and de novo splice-donor site mutation in intron 3 of the GH-1 gene in a patient with isolated growth hormone deficiency.	Katsumata N	Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society	2001	PMID: 11914025
Isolated GH deficiency with dominant inheritance: new mutations, new insights.	Binder G	The Journal of clinical endocrinology and metabolism	2001	PMID: 11502827
Autosomal dominant growth hormone (GH) deficiency type II: the Del32-71-GH deletion mutant suppresses secretion of wild-type GH.	Lee MS	Endocrinology	2000	PMID: 10698162
A novel mutation at the donor splice site of intron 3 of the GH-I gene in a patient with isolated growth hormone deficiency.	Hayashi Y	Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society	1999	PMID: 10629163
Hereditary isolated growth hormone deficiency caused by GH1 gene mutations in Japanese patients.	Kamijo T	Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society	1999	PMID: 10549303
Mutations in intron 3 of GH-1 gene associated with isolated GH deficiency type II in three Japanese families.	Kamijo T	Clinical endocrinology	1999	PMID: 10469016
The molecular genetics of growth hormone deficiency.	Procter AM	Human genetics	1998	PMID: 9799079
De novo mutations of the growth hormone gene: an important cause of congenital isolated growth hormone deficiency?	Massa GG	European journal of pediatrics	1998	PMID: 9578959
Prevalence of human GH-1 gene alterations in patients with isolated growth hormone deficiency.	Wagner JK	Pediatric research	1998	PMID: 9432120
Detection of growth hormone gene defects by dideoxy fingerprinting (ddF).	Miyata I	Endocrine journal	1997	PMID: 9152628
Mechanisms responsible for dominant expression of human growth hormone gene mutations.	Binder G	The Journal of clinical endocrinology and metabolism	1996	PMID: 8923859
A recurring dominant negative mutation causes autosomal dominant growth hormone deficiency--a clinical research center study.	Cogan JD	The Journal of clinical endocrinology and metabolism	1995	PMID: 8530604
Screening for growth hormone (GH) gene splice-site mutations in sporadic cases with severe isolated GH deficiency using ectopic transcript analysis.	Binder G	The Journal of clinical endocrinology and metabolism	1995	PMID: 7714096
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Text-mined citations for rs71640277 ...

These 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 Jun 10, 2023

ClinVar Genomic variation as it relates to human health

NM_000515.5(GH1):c.291+1G>C

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs71640277 ...