ClinVar Genomic variation as it relates to human health
NM_014321.4(ORC6):c.2T>C (p.Met1Thr)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(1); Likely pathogenic(2); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_014321.4(ORC6):c.2T>C (p.Met1Thr)
Variation ID: 253272 Accession: VCV000253272.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q11.2 16: 46689707 (GRCh38) [ NCBI UCSC ] 16: 46723619 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Sep 4, 2016 Feb 14, 2024 Dec 13, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_014321.4:c.2T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_055136.1:p.Met1Thr missense initiator codon variant NR_037620.2:n.49T>C non-coding transcript variant NC_000016.10:g.46689707T>C NC_000016.9:g.46723619T>C NG_028241.1:g.5062T>C NG_029970.1:g.4526A>G - Protein change
- M1T
- Other names
- -
- Canonical SPDI
- NC_000016.10:46689706:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00040 (C)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
The Genome Aggregation Database (gnomAD), exomes 0.00028
Exome Aggregation Consortium (ExAC) 0.00029
1000 Genomes Project 30x 0.00031
Trans-Omics for Precision Medicine (TOPMed) 0.00033
1000 Genomes Project 0.00040
- Comment on variant
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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ORC6 | - | - |
GRCh38 GRCh37 |
140 | 175 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 12, 2019 | RCV000239616.12 | |
Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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Dec 13, 2023 | RCV000579163.16 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(May 05, 2016)
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criteria provided, single submitter
Method: clinical testing
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Meier-Gorlin syndrome 3
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000596182.2
First in ClinVar: Aug 27, 2017 Last updated: Sep 03, 2023 |
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Uncertain significance
(Nov 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000680778.5
First in ClinVar: Feb 13, 2018 Last updated: Nov 25, 2023 |
Comment:
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 … (more)
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) (less)
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Likely pathogenic
(Jan 12, 2019)
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criteria provided, single submitter
Method: clinical testing
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Meier-Gorlin syndrome 3
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000915715.2
First in ClinVar: May 27, 2019 Last updated: Sep 03, 2023 |
Comment:
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 … (more)
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. (less)
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Likely pathogenic
(Dec 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002208688.4
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Aug 30, 2016)
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no assertion criteria provided
Method: literature only
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MEIER-GORLIN SYNDROME 3
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000298176.3
First in ClinVar: Aug 29, 2016 Last updated: Sep 03, 2023 |
Comment on evidence:
In 4 patients with Meier-Gorlin syndrome-3 (MGORS3; 613803), de Munnik et al. (2012) identified compound heterozygosity for 2 mutations in the ORC6 gene: a c.2T-C … (more)
In 4 patients with Meier-Gorlin syndrome-3 (MGORS3; 613803), de Munnik et al. (2012) identified compound heterozygosity for 2 mutations in the ORC6 gene: a c.2T-C transition within the initial met of the transcription start site (MET1?), and a splice site mutation (c.449+5G-A; 607213.0004). (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001797857.2 First in ClinVar: Aug 21, 2021 Last updated: Sep 03, 2023 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001740223.4 First in ClinVar: Jul 07, 2021 Last updated: Sep 03, 2023 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001958405.2 First in ClinVar: Oct 02, 2021 Last updated: Sep 03, 2023 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002038223.2 First in ClinVar: Dec 21, 2021 Last updated: Sep 03, 2023 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Meier-Gorlin syndrome genotype-phenotype studies: 35 individuals with pre-replication complex gene mutations and 10 without molecular diagnosis. | de Munnik SA | European journal of human genetics : EJHG | 2012 | PMID: 22333897 |
Text-mined citations for rs146795505 ...
HelpRecord last updated Jun 23, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.
NCBI staff reviewed the sequence information reported in PubMed 22333897 Table 2 to determine the location of this allele on the current reference sequence.