ClinVar Genomic variation as it relates to human health

The GHRHR c.29T>G (p.Val10Gly) variant is a missense variant that has been reported in a heterozygous state in four individuals with isolated growth hormone deficiency in whom a second variant was not identified (Lessi et al. 2001; Godi et al. 2009). Godi et al. (2009) also identified the p.Val10Gly variant in a heterozygous state in two unaffected family members. The variant was found in one of 1097 control individuals and is reported at a frequency of 0.00027 in the European American population of the Exome Sequencing Project, although this is based on two alleles in a region of poor sequencing coverage. Functional studies showed that the signal peptide is not cleaved in transfected CHO cells expressing the p.Val10Gly variant and that translocation of the protein to the cellular surface is hampered (Godi et al. 2009). Based on the evidence, the p.Val10Gly variant is considered to be of unknown significance but suspicious for pathogenicity for isolated growth hormone deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 10 of the GHRHR protein (p.Val10Gly). This variant is present in population databases (rs139599160, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of growth hormone deficiency sufficient (PMID: 19622623). ClinVar contains an entry for this variant (Variation ID: 360027). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects GHRHR function (PMID: 19622623). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Variant summary: GHRHR c.29T>G (p.Val10Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 154880 control chromosomes (gnomAD). c.29T>G has been reported in the literature in the heterozygous state in individuals affected with Isolated growth hormone deficiency, as well as in unaffected individuals (Godi_2009). This report does not provide unequivocal conclusions about association of the variant with Isolated growth hormone deficiency, type 4. At least one publication reports experimental evidence evaluating an impact on protein function, finding that it disrupts cleavage of the signal peptide and localization to the cell surface (Godi_2009). The following publication has been ascertained in the context of this evaluation (PMID: 19622623). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.