chr5-42699892-G-C

Position:

• chr5-42699892-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D170G) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: GHR NM_000163.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.28

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 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, 4 uncertain in NM_000163.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-42699893-A-G is described in Lovd as [Pathogenic].
• 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 [Likely_pathogenic]. Clinvar id is 8653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-42699892-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GHR	NM_000163.5	c.508G>C	p.Asp170His	missense_variant	6/10	ENST00000230882.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GHR	ENST00000230882.9	c.508G>C	p.Asp170His	missense_variant	6/10	1	NM_000163.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250912 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135566

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 SAS exome AF: 0.0000980

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Laron-type isolated somatotropin defect Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1998	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Dec 07, 2010	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 24, 2023	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. -

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;.;.
MutationTaster	Benign	1.0	A;A;A
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

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: rs121909366; hg19: chr5-42699994;