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

gnomAD frequency: 0.00016  dbSNP: rs143141689

Total submissions: 10

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001382828	SCV001581768	pathogenic	not provided	2024-12-18	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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Ambry Genetics	RCV004955259	SCV005460889	likely pathogenic	Inborn genetic diseases	2024-10-07	criteria provided, single submitter	clinical testing	The c.314G>A (p.R105Q) alteration is located in exon 4 (coding exon 3) of the ORC1 gene. This alteration results from a G to A substitution at nucleotide position 314, causing the arginine (R) at amino acid position 105 to be replaced by a glutamine (Q). Based on data from gnomAD, the A allele has an overall frequency of 0.011% (30/282880) total alleles studied. The highest observed frequency was 0.023% (30/129184) of European (non-Finnish) alleles. This variant has been identified in the homozygous state and/or in conjunction with other ORC1 variants in individuals with microtia, absent or hypoplastic patellae, low-set ears, dysmorphic facial features, respiratory problems, and/or cognitive impairment; in at least one instance, the variants were identified in trans (Guernsey, 2011; Bicknell, 2011; Bicknell, 2011). This amino acid position is highly conserved in available vertebrate species. In multiple assays testing ORC1 function, this variant showed functionally abnormal results (Hossain, 2012; Zhang, 2015) This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000023156	SCV005648584	pathogenic	Meier-Gorlin syndrome 1	2024-04-10	criteria provided, single submitter	clinical testing
OMIM	RCV000023156	SCV000044447	pathogenic	Meier-Gorlin syndrome 1	2011-02-27	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004745166	SCV005360393	pathogenic	ORC1-related disorder	2024-06-07	no assertion criteria provided	clinical testing	The ORC1 c.314G>A variant is predicted to result in the amino acid substitution p.Arg105Gln. This variant was reported in the homozygous and compound heterozygous state in individuals with Meier-Gorlin syndrome (Bicknell et al. 2011. PubMed ID: 21358633; Bicknell et al. 2011. PubMed ID: 21358632; Hossain et al. 2012. PubMed ID: 22855792; Zhang et al. 2015. PubMed ID: 25689043). This variant is reported in 0.023% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.