rs121909366

Variant names:

• chr5-42699892-G-C
• rs121909366
• NM_000163.5:c.508G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PP3_Strong PP5

The NM_000163.5(GHR):​c.508G>C​(p.Asp170His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000828 in 1,449,842 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).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: GHR NM_000163.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 9.28
• Publications: 11 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 1 benign, 4 uncertain in NM_000163.5
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 5-42699892-G-C is Pathogenic according to our data. Variant chr5-42699892-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 8653.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHR	NM_000163.5	c.508G>C	p.Asp170His	missense_variant	Exon 6 of 10	ENST00000230882.9	NP_000154.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GHR	ENST00000230882.9	c.508G>C	p.Asp170His	missense_variant	Exon 6 of 10	1	NM_000163.5	ENSP00000230882.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250912 AF XY: 0.0000148

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000828 AC: 12 AN: 1449842 Hom.: 0 Cov.: 27 AF XY: 0.0000125 AC XY: 9 AN XY: 722034

African (AFR) AF: 0.00 AC: 0 AN: 33280

American (AMR) AF: 0.00 AC: 0 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86032

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1101072

Other (OTH) AF: 0.00 AC: 0 AN: 59974

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Laron-type isolated somatotropin defect Pathogenic:3

Dec 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 22, 2022

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported to be associated with GHR related disorder (ClinVar ID: VCV000008653, PMID:8137822). The variant was co-segregated with Laron dwarfism in multiple affected family members (PMID: 8137822). Different pathogenic/likely pathogenic amino acid change has been reported with supporting evidence at the same codon (PMID:15055350). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.794>=0.6, 3CNET: 0.799>=0.75). A missense variant is a common mechanism associated with Laron dwarfism. It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000120). herefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Dec 07, 2010

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:2 Uncertain:1

Nov 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 170 of the GHR protein (p.Asp170His). This variant is present in population databases (rs121909366, gnomAD 0.01%). This missense change has been observed in individuals with Laron dwarfism (PMID: 8137822). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8653). 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 expected to disrupt GHR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GHR function (PMID: 25101218). This variant disrupts the p.Asp170 amino acid residue in GHR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15055350). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Nov 27, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 8137822, 9851797, 36703223, 37780997, 24833397) -

Dec 17, 2022

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;D;.;D;D;D;D;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;.;D;.;.;D;.;D;D
M_CAP	Benign	0.041	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.011	D
MutationAssessor	Pathogenic	3.2	M;M;.;M;M;M;M;.;.
PhyloP100		9.3
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.3	D;.;.;.;.;.;.;D;.
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;D;D;D;.;.
Vest4		0.96
MutPred		0.91		Loss of stability (P = 0.0447);Loss of stability (P = 0.0447);.;Loss of stability (P = 0.0447);Loss of stability (P = 0.0447);Loss of stability (P = 0.0447);Loss of stability (P = 0.0447);.;Loss of stability (P = 0.0447);
MVP		0.94
MPC		0.34
ClinPred		0.89	D
GERP RS		5.9
Varity_R		0.95
gMVP		0.79
Mutation Taster		=7/93	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121909366; hg19: chr5-42699994;