ClinVar Miner

Submissions for variant NM_004153.4(ORC1):c.314G>A (p.Arg105Gln)

gnomAD frequency: 0.00016  dbSNP: rs143141689
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000023156 SCV000358082 likely pathogenic Meier-Gorlin syndrome 1 2017-04-27 criteria provided, single submitter clinical testing The ORC1 c.314G>A (p.Arg105Gln) missense variant has been reported in two studies in which it is found in a total of seven individuals with Meier-Gorlin syndrome, including in one in a homozygous state and in six (including two siblings) in a compound heterozygous state with a truncating variant or splice acceptor site variant as the second allele (Bicknell et al. 2011; de Munnik et al. 2012). Control data are unavailable for this variant, which is reported at a frequency of 0.00047 in the European American population of the Exome Sequencing Project. Functional studies suggest that the p.Arg105Gln variant abolishes the ability of Orc1 to inhibit Cyclin E-CDK2 kinase activity (Hossain and Stillman 2012) and reduces DNA binding affinity leading to impaired nucleosome interaction (Zhang et al. 2015). Based on the evidence, the p.Arg105Gln variant is classified as pathogenic for Meier-Gorlin syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000302017 SCV000711967 pathogenic Meier-Gorlin syndrome 2016-04-13 criteria provided, single submitter clinical testing The p.Arg105Gln variant in ORC1 has been reported in at least 5 individuals (1 h omozygous and 4 compound heterozygous with other disease-associated variants) wi th clinical features of Meier-Gorlin syndrome (Bicknell 2011, de Munnik 2012). T his variant has also been identified in 10/121,412 of chromosomes by the Exome A ggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs143141689). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functi onal studies provide some evidence that the p.Arg105Gln variant may impact prote in function (Bicknell 2011, Hossain 2012, Zhang 2015). In summary, this variant meets our criteria to be classified as pathogenic for Meier-Gorlin syndrome in a n autosomal recessive manner based upon its co-occurrence with disease-causing v ariants in affected individuals, low frequency in control populations and functi onal evidence.
Invitae RCV001382828 SCV001581768 pathogenic not provided 2023-12-19 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 105 of the ORC1 protein (p.Arg105Gln). This variant is present in population databases (rs143141689, gnomAD 0.02%). This missense change has been observed in individuals with Meier-Gorlin syndrome (PMID: 21358631, 21358632). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30232). 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 not expected to disrupt ORC1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ORC1 function (PMID: 22855792). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001382828 SCV001982423 likely pathogenic not provided 2022-07-19 criteria provided, single submitter clinical testing Published functional studies demonstrate reduced ORC1 DNA binding affinity, leading to impaired ORC1-nucleosome reaction and a defect in regulation of centriole and centrosome copy numbers (Zhang et al., 2015; Hossain et al., 2012); This variant is associated with the following publications: (PMID: 22855792, 23516378, 30609409, 34426522, 14564153, 31980526, 26323792, 33477564, 11477602, 21358632, 23023959, 33761311, 21358633, 22333897, 21358631, 25689043)
Revvity Omics, Revvity RCV000023156 SCV002020581 pathogenic Meier-Gorlin syndrome 1 2021-12-30 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV001382828 SCV002064351 pathogenic not provided 2021-09-07 criteria provided, single submitter clinical testing The sequence change, c.314G>A, in exon 4 results in an amino acid change, p.Arg105Gln. This sequence change has been previously described in the homozygous and compound heterozygous states in individuals and families with ORC1-related Meier-Gorlin syndrome (PMIDs: 21358632, 21358631, 22333897). This sequence change has been described in the gnomAD database with a low frequency of 0.023% in non-Finnish European subpopulation only (dbSNP rs143141689). The p.Arg105Gln change affects a highly conserved amino acid residue located in the BAH domain of the ORC1 protein. Functional studies indicates p.Arg105Gln disrupts the function of the ORC1 protein (PMID: 22855792, 25689043). Collectively this evidence suggests p.Arg105Gln is pathogenic.
OMIM RCV000023156 SCV000044447 pathogenic Meier-Gorlin syndrome 1 2011-02-27 no assertion criteria provided literature only

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