Submissions for variant NM_000163.5(GHR):c.168C>A (p.Cys56Ter)

gnomAD frequency: 0.00001  dbSNP: rs121909359

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317031	SCV004020481	pathogenic	Growth hormone insensitivity syndrome	2023-06-14	criteria provided, single submitter	clinical testing	Variant summary: GHR c.168C>A (p.Cys56X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.6e-05 in 251374 control chromosomes. c.168C>A has been reported in the literature in homozygous and compound heterozygous individuals affected with Growth Hormone Insensitivity (examples: Woods_1997, Shapiro_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28870985, 9360502). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003764539	SCV004618843	pathogenic	not provided	2023-12-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys56*) 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 (rs121909359, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Laron dwarfism (PMID: 1999489). This variant is also known as C38X. ClinVar contains an entry for this variant (Variation ID: 8634). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV003764539	SCV005078204	likely pathogenic	not provided	2023-12-03	criteria provided, single submitter	clinical testing	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: 25525159, 1999489)
OMIM	RCV000009166	SCV000029383	pathogenic	Laron-type isolated somatotropin defect	1991-03-01	no assertion criteria provided	literature only
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000009166	SCV000692131	pathogenic	Laron-type isolated somatotropin defect	2012-12-10	no assertion criteria provided	clinical testing