NM_000823.4(GHRHR):c.527C>T (p.Ala176Val) AND not provided

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Mar 8, 2023
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:: RCV002260860.6

Allele description [Variation Report for NM_000823.4(GHRHR):c.527C>T (p.Ala176Val)]

NM_000823.4(GHRHR):c.527C>T (p.Ala176Val)

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.527C>T (p.Ala176Val)

HGVS:

NC_000007.14:g.30972025C>T
NG_021416.1:g.13005C>T
NM_000823.4:c.527C>TMANE SELECT
NP_000814.2:p.Ala176Val
NC_000007.13:g.31011640C>T
NM_000823.3:c.527C>T

Protein change:

A176V

Links:

dbSNP: rs774281185

NCBI 1000 Genomes Browser:

rs774281185

Molecular consequence:

NM_000823.4:c.527C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002540529	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Nov 1, 2022)	germline	clinical testing	Citation Link,
SCV003245331	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Mar 8, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 31231873, 12534354, 16135671, 33060564, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002540529

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Nov 1, 2022)

germline

clinical testing

Citation Link,

SCV003245331

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Mar 8, 2023)

germline

clinical testing

PubMed (5)
[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

Contribution of functionally assessed GHRHR mutations to idiopathic isolated growth hormone deficiency in patients without GH1 mutations.

Cohen E, Belkacem S, Fedala S, Collot N, Khallouf E, Dastot F, Polak M, Duquesnoy P, Brioude F, Rose S, Viot G, Soleyan A, Carel JC, Sobrier ML, Chanson P, Gatelais F, Heinrichs C, Kaffel N, Coutant R, Savaş Erdeve Ş, Kurnaz E, Aycan Z, et al.

Hum Mutat. 2019 Nov;40(11):2033-2043. doi: 10.1002/humu.23847. Epub 2019 Aug 6.

PubMed [citation]

PMID:: 31231873

A new missense mutation in the growth hormone-releasing hormone receptor gene in familial isolated GH deficiency.

Carakushansky M, Whatmore AJ, Clayton PE, Shalet SM, Gleeson HK, Price DA, Levine MA, Salvatori R.

Eur J Endocrinol. 2003 Jan;148(1):25-30.

PubMed [citation]

PMID:: 12534354

See all PubMed Citations (5)

Details of each submission

From GeneDx, SCV002540529.3

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

Description

Published functional studies demonstrate a damaging effect where p.(A176V) receptor shows reduced ability to respond to GHRH, thus impairing intracellular signals for stimulating GH secretion (Carakushansky et al., 2003; Alba M et al., 2005); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 19622623, 31231873, 16135671, 12534354, 27114065, 23052699)

#	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, SCV003245331.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This missense change has been observed in individuals with growth hormone deficiency (PMID: 12534354, 31231873). It has also been observed to segregate with disease in related individuals. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects GHRHR function (PMID: 12534354, 16135671, 33060564). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GHRHR protein function. ClinVar contains an entry for this variant (Variation ID: 1693449). This variant is present in population databases (rs774281185, gnomAD 0.01%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 176 of the GHRHR protein (p.Ala176Val).

#	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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