rs199588904

Positions:

• chr3-172447705-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_198407.2(GHSR):​c.709A>T​(p.Arg237Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000191 in 1,614,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: GHSR NM_198407.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:9
• Conservation: PhyloP100: 2.89

Genes affected

GHSR (HGNC:4267): (growth hormone secretagogue receptor) This gene encodes a member of the G-protein coupled receptor family. The encoded protein may play a role in energy homeostasis and regulation of body weight. Two identified transcript variants are expressed in several tissues and are evolutionary conserved in fish and swine. One transcript, 1a, excises an intron and encodes the functional protein; this protein is the receptor for the Ghrelin ligand and defines a neuroendocrine pathway for growth hormone release. The second transcript (1b) retains the intron and does not function as a receptor for Ghrelin; however, it may function to attenuate activity of isoform 1a. Mutations in this gene are associated with autosomal idiopathic short stature.[provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.754

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GHSR	NM_198407.2	c.709A>T	p.Arg237Trp	missense_variant	1/2	ENST00000241256.3	NP_940799.1
GHSR	NM_004122.2	c.709A>T	p.Arg237Trp	missense_variant	1/1		NP_004113.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GHSR	ENST00000241256.3	c.709A>T	p.Arg237Trp	missense_variant	1/2	1	NM_198407.2	ENSP00000241256.2
GHSR	ENST00000427970.1	c.709A>T	p.Arg237Trp	missense_variant	1/1	6		ENSP00000395344.1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152078 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000199 AC: 50 AN: 250676 Hom.: 0 AF XY: 0.000236 AC XY: 32 AN XY: 135634

Gnomad AFR exome AF: 0.0000626

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000256

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000201 AC: 294 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.000215 AC XY: 156 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000487

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000196

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152196 Hom.: 0 Cov.: 31 AF XY: 0.0000537 AC XY: 4 AN XY: 74420

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000245 Hom.: 0

Bravo AF: 0.000102

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000189 AC: 23

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 06, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed with a variant on the opposite allele (in trans) in a patient with partial growth hormone deficiency and unexplained episodes of abdominal pain, vomiting, ketosis, and hypoglycemia. Unaffected parents with normal stature were heterozygous carriers (Pantel et al., 2009).; In vitro functional studies show that the R237W mutant has a lower constitutive expression compared to wild type, however, R237W demonstrated normal cell surface expression and a normal ability to bind and respond to ghrelin (Pantel et al., 2009); This variant is associated with the following publications: (PMID: 19789204) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 237 of the GHSR protein (p.Arg237Trp). This variant is present in population databases (rs199588904, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of growth hormone deficiency (PMID: 19789204). ClinVar contains an entry for this variant (Variation ID: 7634). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GHSR protein function. Experimental studies have shown that this missense change affects GHSR function (PMID: 19789204). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Short stature due to growth hormone secretagogue receptor deficiency Pathogenic:1 Uncertain:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2009	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The GHSR c.709A>T (p.Arg237Trp) missense variant was identified in a compound heterozygous state in one individual with short stature and endocrine analysis consistent with partial isolated growth hormone deficiency (Pantel et al. 2009). Family studies revealed that the individual's unaffected mother and an unaffected sibling were heterozygous for the variant. Control data are unavailable for this variant, which is reported at a frequency of 0.00047 in the European-American population of the Exome Sequencing Project. In vitro expression experiments showed that the p.Arg237Trp variant resulted in a partial loss of constitutive activity of the receptor, though the ability to respond to ghrelin and its cell surface expression were preserved. The evidence for this variant is limited. The p.Arg237Trp variant is classified as a variant of unknown significance but suspicious for pathogenicity for partial isolated growth hormone deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 06, 2021	PM2, PP3, BP1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 03, 2020

The alteration results in an amino acid change:_x000D_ _x000D_ The c.709A>T (p.R237W) alteration is located in coding exon 1 of the GHSR gene. This alteration results from a A to T substitution at nucleotide position 709, causing the arginine (R) at amino acid position 237 to be replaced by a tryptophan (W). The alteration is rare in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the c.709A>T alteration was observed in 0.0195% (55/282,042) of total alleles studied. No homozygotes were reported in gnomAD. The alteration has been observed in affected individuals:_x000D_ _x000D_ A 6 year old boy with partial isolated growth hormone deficiency (IGHD) was reported to have compound heterozygous c.709A>T (p.R237W) and c.6G>A (p.W2*) in GHSR (Pantel, 2009). The patient initially had normal birth height and weight. Growth delay (−3.0 SD) was associated with recurrent episodes of abdominal pain, vomiting, ketosis, hypoglycemia, and a low body mass index. Endocrine investigations revealed markedly low levels of IGF-I. He displayed a low growth hormone (GH) response to two provocative tests with GH peaks less than 10 ng/ml and no other pituitary hormone deficiency, consistent with the diagnosis of partial IGHD. The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.R237 amino acid is conserved in available vertebrate species. The alteration is predicted inconclusive by in silico modeling:_x000D_ _x000D_ The in silico prediction for the p.R237W alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.64	D;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.8	M;M
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.0	D;D
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;D
Vest4		0.94
MVP		0.84
MPC		0.45
ClinPred		0.59	D
GERP RS		5.5
Varity_R		0.82
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199588904; hg19: chr3-172165495;