Submissions for variant NM_198407.2(GHSR):c.531C>A (p.Pro177=)

gnomAD frequency: 0.00334  dbSNP: rs4988509

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000865176	SCV001006104	benign	not provided	2024-01-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001145273	SCV001305924	likely benign	Short stature due to growth hormone secretagogue receptor deficiency	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
CeGaT Center for Human Genetics Tuebingen	RCV000865176	SCV005051644	likely benign	not provided	2024-05-01	criteria provided, single submitter	clinical testing	GHSR: BP4, BP7, BS2
Breakthrough Genomics, Breakthrough Genomics	RCV000865176	SCV005262929	likely benign	not provided		criteria provided, single submitter	not provided
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000865176	SCV001552465	uncertain significance	not provided		no assertion criteria provided	clinical testing	The GHSR p.Pro177Pro variant was identified in dbSNP (ID: rs4988509) but was not identified in ClinVar, Cosmic or LOVD 3.0. The p.Pro177Pro synonymous substitution was identified in a cohort of 15,854 Danes in a study aiming to identify associations between GHSR variants and obesity, however this variant was not further analyzed (Gjesing_2010_PMID: 20404923). The variant was also reported in a case-control study of height but was not analyzed (Gueorguiev_2009_PMID: 18945286). The variant was identified in control databases in 979 of 281750 chromosomes (4 homozygous) at a frequency of 0.003475 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 772 of 128364 chromosomes (freq: 0.006014), European (Finnish) in 122 of 25046 chromosomes (freq: 0.004871), Other in 22 of 7198 chromosomes (freq: 0.003056), African in 20 of 24852 chromosomes (freq: 0.000805), Latino in 22 of 35410 chromosomes (freq: 0.000621), South Asian in 17 of 30598 chromosomes (freq: 0.000556) and Ashkenazi Jewish in 4 of 10340 chromosomes (freq: 0.000387); it was not observed in the East Asian population. The p.Pro177Pro variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site, however 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000865176	SCV001797535	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000865176	SCV001975853	likely benign	not provided		no assertion criteria provided	clinical testing