ClinVar Miner

Submissions for variant NM_004153.4(ORC1):c.266T>C (p.Phe89Ser)

gnomAD frequency: 0.00001  dbSNP: rs387906827
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002513182 SCV003523294 uncertain significance not provided 2022-10-30 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 89 of the ORC1 protein (p.Phe89Ser). This variant is present in population databases (rs387906827, gnomAD 0.0009%). This missense change has been observed in individuals with Meier-Gorlin syndrome (PMID: 21358633, 31274184). ClinVar contains an entry for this variant (Variation ID: 30231). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ORC1 function (PMID: 22855792). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences RCV003398563 SCV004109995 likely pathogenic ORC1-related disorder 2023-07-28 criteria provided, single submitter clinical testing The ORC1 c.266T>C variant is predicted to result in the amino acid substitution p.Phe89Ser. This variant was reported in the homozygous state in two apparently unrelated individuals with microcephalic primordial dwarfism and/or Meier–Gorlin syndrome (Bicknell. 2011. PubMed ID: 21358633; de Munnik. 2012. PubMed ID: 22333897; Vojtková. 2019. PubMed ID: 31274184). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-52863493-A-G). This variant is interpreted as likely pathogenic.
OMIM RCV000023155 SCV000044446 pathogenic Meier-Gorlin syndrome 1 2011-02-27 no assertion criteria provided literature only

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