Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV001156476 | SCV001317975 | uncertain significance | Obesity due to prohormone convertase I deficiency | 2017-04-27 | criteria provided, single submitter | clinical testing | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. |
| Fulgent Genetics, |
RCV002497582 | SCV002806880 | uncertain significance | Body mass index quantitative trait locus 12; Obesity due to prohormone convertase I deficiency | 2022-01-24 | criteria provided, single submitter | clinical testing | |
| Clinical Genetics, |
RCV001700981 | SCV001925716 | uncertain significance | not provided | no assertion criteria provided | clinical testing | ||
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV001700981 | SCV001973448 | uncertain significance | not provided | no assertion criteria provided | clinical testing | ||
| Prevention |
RCV003938522 | SCV004750509 | uncertain significance | PCSK1-related disorder | 2024-02-21 | no assertion criteria provided | clinical testing | The PCSK1 c.541T>C variant is predicted to result in the amino acid substitution p.Tyr181His. This variant has been detected in the heterozygous state in several individuals with obesity but also in control subjects (Creemers et al. 2012. PubMed ID: 22210313; Kleinendorst et al. 2018. PubMed ID: 29970488; Van Dijck et al. 2022. PubMed ID: 36292633). The p.Tyr181His substitution did not influence PCSK1 enzymatic activity in engineered cell lines, but it did result in mildly decreased propeptide cleavage—a property required for activation in native cells (Creemers et al. 2012. PubMed ID: 22210313). In the same study, case-control analysis was under-powered, but suggested the variant may be associated with heterozygous obesity susceptibility; however, this was disputed in a different study (Creemers et al. 2012. PubMed ID: 22210313; Van Dijck et al. 2022. PubMed ID: 36292633). Another in vitro functional study showed suggestive evidence of loss of function (Table 3 and Supplemental Data Set, Shah et al. 2023. PubMed ID: 36864747). This variant is reported in 0.021% of alleles in individuals of European (non-Finnish) descent in gnomAD. Although we suspect this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |