Submissions for variant NM_000823.4(GHRHR):c.527C>T (p.Ala176Val)

gnomAD frequency: 0.00002  dbSNP: rs774281185

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV002260860	SCV002540529	likely pathogenic	not provided	2022-11-01	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect where p.(A176V) receptor shows reduced ability to respond to GHRH, thus impairing intracellular signals for stimulating GH secretion (Carakushansky et al., 2003; Alba M et al., 2005); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 19622623, 31231873, 16135671, 12534354, 27114065, 23052699)
Labcorp Genetics (formerly Invitae), Labcorp	RCV002260860	SCV003245331	likely pathogenic	not provided	2023-03-08	criteria provided, single submitter	clinical testing	This missense change has been observed in individuals with growth hormone deficiency (PMID: 12534354, 31231873). It has also been observed to segregate with disease in related individuals. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects GHRHR function (PMID: 12534354, 16135671, 33060564). 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 not expected to disrupt GHRHR protein function. ClinVar contains an entry for this variant (Variation ID: 1693449). This variant is present in population databases (rs774281185, gnomAD 0.01%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 176 of the GHRHR protein (p.Ala176Val).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317586	SCV004020747	likely pathogenic	Isolated growth hormone deficiency, type 4	2023-06-06	criteria provided, single submitter	clinical testing	Variant summary: GHRHR c.527C>T (p.Ala176Val) results in a non-conservative amino acid change located in the GPCR, family 2-like, transmembrane domain (IPR017981) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251454 control chromosomes (gnomAD). c.527C>T has been reported in the literature in multiple individuals affected with Isolated growth hormone deficiency (examples: Carakushansky_2003, Marui_2012, Birla_2016, Cohen_2019). These data indicate that the variant is very likely to be associated with disease. Multiple publications have reported experimental evidence that the variant protein reduced the ability to respond to GHRH, and impaired intracellular signals for stimulating GH secretion (examples: Carakushansky_2003 and Alba_2005). The following publications have been ascertained in the context of this evaluation (PMID: 16135671, 27114065, 12534354, 31231873, 23052699). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.