5-42699888-T-G

Variant names:

• chr5-42699888-T-G
• rs121909373
• NM_000163.5:c.504T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_000163.5(GHR):​c.504T>G​(p.His168Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 1,607,412 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H168P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GHR NM_000163.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 0.730
• Publications: 3 publications found

Genes affected

GHR (HGNC:4263): (growth hormone receptor) This gene encodes a member of the type I cytokine receptor family, which is a transmembrane receptor for growth hormone. Binding of growth hormone to the receptor leads to receptor dimerization and the activation of an intra- and intercellular signal transduction pathway leading to growth. Mutations in this gene have been associated with Laron syndrome, also known as the growth hormone insensitivity syndrome (GHIS), a disorder characterized by short stature. In humans and rabbits, but not rodents, growth hormone binding protein (GHBP) is generated by proteolytic cleavage of the extracellular ligand-binding domain from the mature growth hormone receptor protein. Multiple alternatively spliced transcript variants have been found for this gene.[provided by RefSeq, Jun 2011]

GHR Gene-Disease associations (from GenCC):

• Laron syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• short stature due to partial GHR deficiency

  Inheritance: Unknown, AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_000163.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925
• PP5: Variant 5-42699888-T-G is Pathogenic according to our data. Variant chr5-42699888-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 8663.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000163.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHR	NM_000163.5	MANE Select	c.504T>G	p.His168Gln	missense	Exon 6 of 10	NP_000154.1
	GHR	NM_001242399.2		c.525T>G	p.His175Gln	missense	Exon 6 of 10	NP_001229328.1
	GHR	NM_001242400.2		c.504T>G	p.His168Gln	missense	Exon 7 of 11	NP_001229329.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHR	ENST00000230882.9	TSL:1 MANE Select	c.504T>G	p.His168Gln	missense	Exon 6 of 10	ENSP00000230882.4
	GHR	ENST00000620156.4	TSL:5	c.525T>G	p.His175Gln	missense	Exon 6 of 10	ENSP00000483403.1
	GHR	ENST00000537449.5	TSL:5	c.504T>G	p.His168Gln	missense	Exon 6 of 10	ENSP00000442206.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250924 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455178 Hom.: 0 Cov.: 27 AF XY: 0.00000138 AC XY: 1 AN XY: 724444

African (AFR) AF: 0.00 AC: 0 AN: 33364

American (AMR) AF: 0.00 AC: 0 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1106006

Other (OTH) AF: 0.00 AC: 0 AN: 60140

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74374

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000624 Hom.: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Jun 14, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies suggest a damaging effect on downstream signal transduction, but the mechanism remains unclear (Fang et al., 2007); In-silico analysis using splice predictors is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17405847)

Sep 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 8663). This variant is also known as p.His150Gln. This missense change has been observed in individual(s) with autosomal recessive Laron syndrome and/or Laron syndrome (PMID: 17405847). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121909373, gnomAD 0.002%). This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 168 of the GHR protein (p.His168Gln). 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. Experimental studies have shown that this missense change affects GHR function (PMID: 17405847). 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 GHR protein function.

Laron-type isolated somatotropin defect Pathogenic:1

Jun 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not specified Uncertain:1

Jun 24, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GHR c.504T>G (p.His168Gln) results in a non-conservative amino acid change located in the Fibronectin type-III domain profile (IPR003961) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 4e-06 in 250924 control chromosomes. c.504T>G has been reported in the literature in the compound heterozygous state in 2 siblings affected with Laron syndrome in which segregation was established (example: Fang_2007). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence demonstrating an impact on protein function. The variant was found to have normal growth hormone (GH) binding, but exhibited a moderate reduction in GH-induced STAT5b activation in vitro in response to physiological concentrations of GH, which was ameliorated at higher doses of GH and did not impair STAT5b-dependent gene expression. The authors suggest the variant may be associated with a defect in transducing GH-induced signal in response to physiological concentrations of GH in vivo. This proposed defect was also observed to a mild degree in primary dermal fibroblasts from an individual carrying the variant of interest in the compound heterozygous state (example: Fang_2007). The following publication has been ascertained in the context of this evaluation (PMID: 17405847). ClinVar contains an entry for this variant (Variation ID: 8663). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D
Eigen	Benign	0.0084
Eigen_PC	Benign	-0.012
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.73
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.042	D
Polyphen		0.42	B
Vest4		0.71
MutPred		0.79		Loss of glycosylation at S163 (P = 0.1838)
MVP		0.96
MPC		0.32
ClinPred		0.73	D
GERP RS		2.1
Varity_R		0.68
gMVP		0.52
Mutation Taster		=22/78	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs121909373; hg19: chr5-42699990;