Submissions for variant NM_000823.4(GHRHR):c.29T>G (p.Val10Gly)

gnomAD frequency: 0.00025  dbSNP: rs139599160

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000377318	SCV000468744	uncertain significance	Isolated growth hormone deficiency type IB	2016-07-27	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001795994	SCV002255604	uncertain significance	not provided	2021-11-14	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479107	SCV004222746	uncertain significance	not specified	2023-11-16	criteria provided, single submitter	clinical testing	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.
Breakthrough Genomics, Breakthrough Genomics	RCV001795994	SCV005188483	uncertain significance	not provided		criteria provided, single submitter	not provided
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001795994	SCV002035711	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001795994	SCV002037262	uncertain significance	not provided		no assertion criteria provided	clinical testing