NM_000823.4(GHRHR):c.57+1G>A AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jul 2, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001568303.7

Allele description [Variation Report for NM_000823.4(GHRHR):c.57+1G>A]

NM_000823.4(GHRHR):c.57+1G>A

Gene:

GHRHR:growth hormone releasing hormone receptor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p14.3

Genomic location:

Preferred name:

NM_000823.4(GHRHR):c.57+1G>A

HGVS:

NC_000007.14:g.30964126G>A
NG_021416.1:g.5106G>A
NM_000823.4:c.57+1G>AMANE SELECT
NC_000007.13:g.31003741G>A
NM_000823.3:c.57+1G>A

Note:

ClinGen staff contributed the HGVS expression for this variant.

Nucleotide change:

IVS1, G-A, +1

Links:

OMIM: 139191.0002; dbSNP: rs2302022

NCBI 1000 Genomes Browser:

rs2302022

Molecular consequence:

NM_000823.4:c.57+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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Rattus norvegicus glypican 4 (Gpc4), mRNA
Rattus norvegicus glypican 4 (Gpc4), mRNA
gi|62078948|ref|NM_001014108.1|

Nucleotide
PREDICTED: Rattus norvegicus glypican 4 (Gpc4), transcript variant X1, mRNA
PREDICTED: Rattus norvegicus glypican 4 (Gpc4), transcript variant X1, mRNA
gi|2678975833|ref|XM_006257580.5|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001792146	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jul 2, 2024)	germline	clinical testing	Citation Link,
SCV003285506	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 19, 2021)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 10084571, 23052699, 16199547, 12444890, 16355809, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001792146

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jul 2, 2024)

germline

clinical testing

Citation Link,

SCV003285506

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 19, 2021)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Familial dwarfism due to a novel mutation of the growth hormone-releasing hormone receptor gene.

Salvatori R, Hayashida CY, Aguiar-Oliveira MH, Phillips JA 3rd, Souza AH, Gondo RG, Toledo SP, Conceicão MM, Prince M, Maheshwari HG, Baumann G, Levine MA.

J Clin Endocrinol Metab. 1999 Mar;84(3):917-23.

PubMed [citation]

PMID:: 10084571

GH-releasing hormone receptor gene: a novel splice-disrupting mutation and study of founder effects.

Marui S, Trarbach EB, Boguszewski MC, França MM, Jorge AA, Inoue H, Nishi MY, de Lacerda Filho L, Aguiar-Oliveira MH, Mendonca BB, Arnhold IJ.

Horm Res Paediatr. 2012;78(3):165-72. doi: 10.1159/000342760. Epub 2012 Oct 10.

PubMed [citation]

PMID:: 23052699

See all PubMed Citations (6)

Details of each submission

From GeneDx, SCV001792146.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 28456063, 31902114, 32935264, 23052699, 24057284, 24398366, 10084571, 25761575, 27552668, 24272598, 30959475, 29571594, 30860584, 31980526, 28428227, 28432269, 11443201, 16522693, 16355809, 10822217)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003285506.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 15990). Disruption of this splice site has been observed in individuals with growth hormone deficiency (PMID: 10084571, 23052699). It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects a donor splice site in intron 1 of the GHRHR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GHRHR are known to be pathogenic (PMID: 12444890, 16355809).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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