Submissions for variant NM_000163.5(GHR):c.703C>T (p.Arg235Ter)

gnomAD frequency: 0.00008  dbSNP: rs121909363

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000760385	SCV000890250	pathogenic	not provided	2023-07-18	criteria provided, single submitter	clinical testing	Reported in the heterozgyous state in a patient with severe growth retardation and growth hormone insensitivity without typical craniofacial or somatic features of Laron syndrome, and RNA studies in patient fibroblasts suggested that mutant transcripts are subject to nonsense-mediated decay (Gorbenko del Blanco et al., 2012); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 16932322, 25525159, 8504296, 8488849, 25411237, 22117696, 28743110)
Invitae	RCV000760385	SCV003525658	pathogenic	not provided	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg235*) in the GHR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GHR are known to be pathogenic (PMID: 1999489, 8488849). This variant is present in population databases (rs121909363, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Laron syndrome (PMID: 8504296). This variant is also known as R217W. ClinVar contains an entry for this variant (Variation ID: 8639). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000009171	SCV004048443	pathogenic	Laron-type isolated somatotropin defect		criteria provided, single submitter	clinical testing	The c.724C>T (p.Arg242Ter) variant in the GHR gene has been reported previously in the homozygous state in individuals with a clinical and biochemical phenotype consistent with Laron syndrome (Amselem et al., 1993; Berg et al., 1993; Storr et al., 2015). The stop gained variant in GHR gene has been reported to the ClinVar database as Pathogenic. The variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.002% in the gnomAD exomes database. This variant has been shown to cause loss of normal protein function through nonsense-mediated mRNA decay (Gorbenko del Blanco et al., 2012). The nucleotide change in GHR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Breakthrough Genomics, Breakthrough Genomics	RCV000009171	SCV005088804	pathogenic	Laron-type isolated somatotropin defect	2020-01-02	criteria provided, single submitter	clinical testing	This variant is predicted to cause premature termination of the protein (p.Arg235Ter). The truncated protein is likely to lack the transmembrane domain and cytoplasmic domain of the protein [UniProt]; this will likely result in loss-of-function. The variant has been previously reported in individuals affected with Laron syndrome [PMID: 8488849, 17598975].
OMIM	RCV000009171	SCV000029388	pathogenic	Laron-type isolated somatotropin defect	1993-05-01	no assertion criteria provided	literature only
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000009171	SCV000692134	pathogenic	Laron-type isolated somatotropin defect	2013-08-07	no assertion criteria provided	clinical testing