Submissions for variant NM_014321.4(ORC6):c.2T>C (p.Met1Thr)

gnomAD frequency: 0.00028  dbSNP: rs146795505

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000239616	SCV000596182	pathogenic	Meier-Gorlin syndrome 3	2016-05-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000579163	SCV000680778	uncertain significance	not provided	2023-11-06	criteria provided, single submitter	clinical testing	Initiation codon variant in a gene for which loss of function is not a known mechanism of disease; This variant is associated with the following publications: (PMID: 29431110, 34426522, 31589614, 36012502, 22333897)
Illumina Laboratory Services, Illumina	RCV000239616	SCV000915715	likely pathogenic	Meier-Gorlin syndrome 3	2019-01-12	criteria provided, single submitter	clinical testing	The ORC6 c.2T>C (p.Met1?) variant is a stop-lost variant that is predicted to result in an elongation of the protein. This variant has been reported in one study and is found in a compound heterozygous state in four individuals from three families with Meier-Gorlin syndrome (De Munnik et al. 2012). The p.Met1? variant is reported at a frequency of 0.000601 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence, the p.Met1? variant is classified likely pathogenic for Meier-Gorlin syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000579163	SCV002208688	likely pathogenic	not provided	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the ORC6 mRNA. The next in-frame methionine is located at codon 20. This variant is present in population databases (rs146795505, gnomAD 0.06%). Disruption of the initiator codon has been observed in individuals with Meier–Gorlin syndrome (PMID: 22333897). ClinVar contains an entry for this variant (Variation ID: 253272). 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	RCV000239616	SCV000298176	pathogenic	Meier-Gorlin syndrome 3	2016-08-30	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000579163	SCV001740223	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000579163	SCV001797857	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000579163	SCV001958405	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000579163	SCV002038223	likely pathogenic	not provided		no assertion criteria provided	clinical testing