NM_000163.5:c.703C>T

Variant names:

• chr5-42711291-C-T
• rs121909363
• NM_000163.5:c.703C>T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_Very_Strong

The NM_000163.5(GHR):​c.703C>T​(p.Arg235*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,612,586 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004048443: This variant has been shown to cause loss of normal protein function through nonsense-mediated mRNA decay (Gorbenko del Blanco et al., 2012).; SCV000890250: RNA studies in patient fibroblasts suggested that mutant transcripts are subject to nonsense-mediated decay (Gorbenko del Blanco et al., 2012)". Synonymous variant affecting the same amino acid position (i.e. R235R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: GHR NM_000163.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 1.44
• Publications: 7 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• short stature due to partial GHR deficiency

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

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV004048443: This variant has been shown to cause loss of normal protein function through nonsense-mediated mRNA decay (Gorbenko del Blanco et al., 2012).; SCV000890250: RNA studies in patient fibroblasts suggested that mutant transcripts are subject to nonsense-mediated decay (Gorbenko del Blanco et al., 2012)
• PP5: Variant 5-42711291-C-T is Pathogenic according to our data. Variant chr5-42711291-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 8639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHR	NM_000163.5	MANE Select	c.703C>T	p.Arg235*	stop_gained	Exon 7 of 10	NP_000154.1	P10912-1
	GHR	NM_001242399.2		c.724C>T	p.Arg242*	stop_gained	Exon 7 of 10	NP_001229328.1	A0A087X0H5
	GHR	NM_001242400.2		c.703C>T	p.Arg235*	stop_gained	Exon 8 of 11	NP_001229329.1	P10912-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHR	ENST00000230882.9	TSL:1 MANE Select	c.703C>T	p.Arg235*	stop_gained	Exon 7 of 10	ENSP00000230882.4	P10912-1
	GHR	ENST00000620156.4	TSL:5	c.724C>T	p.Arg242*	stop_gained	Exon 7 of 10	ENSP00000483403.1	A0A087X0H5
	GHR	ENST00000537449.5	TSL:5	c.703C>T	p.Arg235*	stop_gained	Exon 7 of 10	ENSP00000442206.2	P10912-1

Frequencies

GnomAD3 genomes AF: 0.0000658 AC: 10 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251378 AF XY: 0.00000736

Gnomad AFR exome AF: 0.000123

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000822 AC: 12 AN: 1460500 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 726660

African (AFR) AF: 0.000120 AC: 4 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1110786

Other (OTH) AF: 0.00 AC: 0 AN: 60340

GnomAD4 genome AF: 0.0000658 AC: 10 AN: 152086 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74292

African (AFR) AF: 0.000169 AC: 7 AN: 41418

American (AMR) AF: 0.00 AC: 0 AN: 15260

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000585 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Laron-type isolated somatotropin defect (4)
2	-	-	not provided (2)
1	-	-	Laron-type isolated somatotropin defect;C0745103:Hypercholesterolemia, familial, 1;C1858656:Short stature due to partial GHR deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Benign	0.71	D
PhyloP100		1.4
Vest4		0.94
GERP RS		3.4
Mutation Taster		=0/200	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: rs121909363; hg19: chr5-42711393; COSMIC: COSV105854608; COSMIC: COSV105854608;