rs121909362

chr5-42699919-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM1 BP4_Moderate BS1 BS2

The NM_000163.5(GHR):c.535C>T(p.Arg179Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00458 in 1,595,748 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign 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. R179H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0040 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0046 (19 hom.)
• Consequence: GHR NM_000163.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4 B:5
• Conservation: PhyloP100: 1.30

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 Benign. Variant got -8 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000163.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.085534275).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00402 (612/152228) while in subpopulation AMR AF= 0.00759 (116/15290). AF 95% confidence interval is 0.00647. There are 3 homozygotes in gnomad4. There are 307 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GHR	NM_000163.5	c.535C>T	p.Arg179Cys	missense_variant	6/10	ENST00000230882.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GHR	ENST00000230882.9	c.535C>T	p.Arg179Cys	missense_variant	6/10	1	NM_000163.5	P1

Frequencies

GnomAD3 genomes AF: 0.00402 AC: 612 AN: 152110 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000966

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00760

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00227

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00597

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00391 AC: 980 AN: 250850 Hom.: 3 AF XY: 0.00396 AC XY: 537 AN XY: 135536

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00273

Gnomad ASJ exome AF: 0.00239

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00310

Gnomad FIN exome AF: 0.00287

Gnomad NFE exome AF: 0.00584

Gnomad OTH exome AF: 0.00458

GnomAD4 exome AF: 0.00464 AC: 6702 AN: 1443520 Hom.: 19 Cov.: 25 AF XY: 0.00462 AC XY: 3323 AN XY: 719324

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00305

Gnomad4 ASJ exome AF: 0.00177

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00301

Gnomad4 FIN exome AF: 0.00337

Gnomad4 NFE exome AF: 0.00529

Gnomad4 OTH exome AF: 0.00402

GnomAD4 genome AF: 0.00402 AC: 612 AN: 152228 Hom.: 3 Cov.: 33 AF XY: 0.00413 AC XY: 307 AN XY: 74420

Gnomad4 AFR AF: 0.000963

Gnomad4 AMR AF: 0.00759

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.00227

Gnomad4 NFE AF: 0.00597

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00555 Hom.: 9

Bravo AF: 0.00385

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00814 AC: 70

ExAC AF: 0.00409 AC: 496

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:4 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 13, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2021	This variant is associated with the following publications: (PMID: 7565946, 17462934, 8504296, 28498917, 29748515, 29073591, 27914676, 32935225) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	GHR: BS1 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Short stature due to partial GHR deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 26, 1995

- -

Laron-type isolated somatotropin defect;C0745103:Hypercholesterolemia, familial, 1;C1858656:Short stature due to partial GHR deficiency;C4707848:Short stature due to growth hormone secretagogue receptor deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

GHR-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 16, 2023

The GHR c.535C>T variant is predicted to result in the amino acid substitution p.Arg179Cys. This variant was reported in homozygous state in an individual with Laron dwarfism (Amselem et al. 1993. PubMed ID: 8504296) and in heterozygous state in several individuals with idiopathic short stature (Goddard et al. 1995. PubMed ID: 7565946; Sjoberg et al. 2001. PubMed ID: 11549678; Meyer et al. 2007. PubMed ID: 17462934; Barrio-Ollero et al. 2016. PubMed ID: 27914676; Mohammadian Khonsari et al. 2020. PubMed ID: 32935225). This variant is reported in 0.59% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-42700021-C-T). This frequency is higher than would be expected for causative variants in this gene. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Laron-type isolated somatotropin defect;C1858656:Short stature due to partial GHR deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

May 09, 2016

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Nov 01, 2023

Variant summary: GHR c.535C>T (p.Arg179Cys) results in a non-conservative amino acid change located in the fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0039 in 282250 control chromosomes in the gnomAD database, including 5 homozygotes. The observed variant frequency is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in GHR causing Growth Hormone Insensitivity phenotype (0.0035). These data suggest that the variant is benign. c.535C>T has been reported in the literature as a biallelic genotype in individuals affected with or suspected of Growth Hormone Insensitivity (e.g. Amselem_1993, Goddard_1995, Woods_1997). However, these reports do not provide unequivocal conclusions about association of the variant with Growth Hormone Insensitivity. At least one publication reports experimental evidence evaluating an impact on protein function and found that the variant had a dissociation constant approximately 2-fold higher than that reported for the WT protein, however the impact on GHR activity in vitro was not examined (Goddard_1995). The following publications have been ascertained in the context of this evaluation (PMID: 8504296, 7565946, 11502828, 9360502). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Four submitters classified the variant as uncertain significance and three classified it as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Laron-type isolated somatotropin defect Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Uncertain	0.12
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;T;.;T;T;T;T;.;.
Eigen	Benign	-0.034
Eigen_PC	Benign	0.012
FATHMM_MKL	Uncertain	0.82	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.086	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	1.0	L;L;.;L;L;L;L;.;.
MutationTaster	Benign	0.057	A;A;A
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.79	N;.;.;.;.;.;.;N;.
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Polyphen		0.72	P;P;.;P;P;P;P;.;.
Vest4		0.65
MVP		0.98
MPC		0.061
ClinPred		0.047	T
GERP RS		3.2
Varity_R		0.71
gMVP		0.68

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: rs121909362; hg19: chr5-42700021; COSMIC: COSV99039086;