ClinVar Miner

Submissions for variant NM_004153.4(ORC1):c.2159G>A (p.Arg720Gln)

gnomAD frequency: 0.00002  dbSNP: rs387906828
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV001818177 SCV002064362 likely pathogenic not provided 2021-09-07 criteria provided, single submitter clinical testing The sequence change, c.2159G>A, in exon 15 results in an amino acid change, p.Arg720Gln. This sequence change has been previously described in the compound heterozygous state with p.Arg105Gln in an individual with ORC1-related disorder (PMID: 21358633). This sequence change has been described in the gnomAD database with a low frequency of 0.010% in non-Finnish European subpopulation only (dbSNP rs387906828). The p.Arg720Gln change affects a highly conserved amino acid residue of the ORC1 protein. The p.Arg720Gln substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Functional studies of cell line derived from patient carrying p.Arg720Gln/p.R105Q shows p.Arg720Gln/p.R105Q disrupts the function of the ORC1 protein (PMID: 21358633). Collectively this evidence suggests p.Arg720Gln is likely pathogenic.
Invitae RCV001818177 SCV002295255 likely pathogenic not provided 2023-11-20 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 720 of the ORC1 protein (p.Arg720Gln). This variant is present in population databases (rs387906828, gnomAD 0.01%). This missense change has been observed in individual(s) with Meier-Gorlin syndrome (PMID: 21358633; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 30233). 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 ORC1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ORC1 function (PMID: 28112645). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
OMIM RCV000023157 SCV000044448 pathogenic Meier-Gorlin syndrome 1 2011-02-27 no assertion criteria provided literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.