Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001851886 | SCV002240490 | pathogenic | not provided | 2023-04-09 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GHRHR function (PMID: 11232012, 31231873). 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 GHRHR protein function. ClinVar contains an entry for this variant (Variation ID: 15991). This missense change has been observed in individuals with growth hormone deficiency (PMID: 11232012, 31231873). It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 144 of the GHRHR protein (p.Leu144His). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000017362 | SCV004100238 | pathogenic | Isolated growth hormone deficiency, type 4 | 2023-09-28 | criteria provided, single submitter | clinical testing | Variant summary: GHRHR c.431T>A (p.Leu144His) results in a non-conservative amino acid change located in the GPCR, family 2-like, 7TM 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 2.4e-05 in 166580 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.431T>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Isolated growth hormone deficiency, type 4 (e.g., Salvatori_2001, Correa_2017, Cohen_2019). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function, finding that the variant resulted in the failure to show a cAMP response, likely due to disrupted ligand binding (e.g., Salvatori_2001, Alba_2005). The following publications have been ascertained in the context of this evaluation (PMID: 15196883, 31231873, 29412390, 11232012). One submitter has reported clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| OMIM | RCV000017362 | SCV000037634 | pathogenic | Isolated growth hormone deficiency, type 4 | 2001-01-01 | no assertion criteria provided | literature only |