Submissions for variant NM_000163.5(GHR):c.508G>C (p.Asp170His)

gnomAD frequency: 0.00001  dbSNP: rs121909366

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
3billion	RCV000009185	SCV002318733	likely pathogenic	Laron-type isolated somatotropin defect	2022-03-22	criteria provided, single submitter	clinical testing	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.
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV002508773	SCV002818185	pathogenic	not provided	2022-12-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002508773	SCV004293721	pathogenic	not provided	2023-11-24	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000009185	SCV000029402	pathogenic	Laron-type isolated somatotropin defect	1998-12-01	no assertion criteria provided	literature only
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000009185	SCV000692133	pathogenic	Laron-type isolated somatotropin defect	2010-12-07	no assertion criteria provided	clinical testing