Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Chan Lab, |
RCV000156965 | SCV000206686 | likely pathogenic | Hypogonadotropic hypogonadism 7 with or without anosmia | 2014-11-01 | criteria provided, single submitter | case-control | |
| 3billion | RCV002250579 | SCV002521847 | likely pathogenic | Hypogonadotropic hypogonadism 3 with or without anosmia | 2022-05-22 | criteria provided, single submitter | clinical testing | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 18559922). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.52; 3Cnet: 0.88). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PROKR2 related disorder (ClinVar ID: VCV000180158 / PMID: 18559922). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. |
| Fulgent Genetics, |
RCV002250579 | SCV002808496 | likely pathogenic | Hypogonadotropic hypogonadism 3 with or without anosmia | 2022-02-02 | criteria provided, single submitter | clinical testing | |
| Athena Diagnostics | RCV002505183 | SCV002817207 | pathogenic | not provided | 2019-07-02 | criteria provided, single submitter | clinical testing | This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls (PMID: 28209183, 18559922, http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant reduces the downstream signaling effects of this receptor, thus disrupting the normal function of the protein (PMID: 18559922, 29161432).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. |
| Labcorp Genetics |
RCV002505183 | SCV003241475 | uncertain significance | not provided | 2023-11-28 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 188 of the PROKR2 protein (p.Ser188Leu). This variant is present in population databases (rs376239580, gnomAD 0.01%). This missense change has been observed in individual(s) with absent puberty, disorders of sex development, hypogonadotropic hypogonadism, Kallman syndrome, and/or micropenis (PMID: 18559922, 27899157, 28209183, 28754744, 31781422, 33587123, 34348883). ClinVar contains an entry for this variant (Variation ID: 180158). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PROKR2 protein function. Experimental studies have shown that this missense change affects PROKR2 function (PMID: 18559922, 24830383, 29161432, 36694982). 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. |