ClinVar Miner

Submissions for variant NM_004153.4(ORC1):c.314G>A (p.Arg105Gln) (rs143141689)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,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, Partners HealthCare 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.
OMIM RCV000023156 SCV000044447 pathogenic Meier-Gorlin syndrome 1 2011-02-27 no assertion criteria provided literature only

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