Gene/Disease Pair: | =$Gene?>DNMT1 : =$Disease?>DNMT1 Methylopathy |
HGNC:2976 | OrphaNet: ORPHA314404 | OMIM:604121 | |
Mode of Inheritance: | Autosomal dominant inheritance (HP:0000006) |
Genetic Evidence
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Case-Level Data
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Evidence Type | Case Information Type | Guidelines | Scores | PMIDs/Notes | ||||||
Default | Range | Max | Points | Tally | ||||||||
Variant Evidence
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Autosomal Dominant or X-linked Disorder | Variant is de novo | 2 | 0-3 | 12 |
=$GeneticEvidence2V?>
5.0
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=$GeneticEvidence2Tally?>5 |
=PrintWrapperPmid("GeneticEvidence2", $GeneticEvidence2Pmid) ?>
Winkelmann J et al. 2012 May 15 (PMID:22328086); Pedroso JL et al. 2013 Aug 1 (PMID:23904686); Moghadam KK et al. 2014 Jun (PMID:24727570); Baets J et al. 2015 Apr (PMID:25678562);
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Proband with predicted or proven null variant | 1.5 | 0-2 | 10 | =$GeneticEvidence3V?> | =$GeneticEvidence3Tally?> | =PrintWrapperPmid("GeneticEvidence3", $GeneticEvidence3Pmid) ?> | ||||||
Proband with other variant type with some evidence of gene impact | 0.5 | 0-1.5 | 7 | =$GeneticEvidence1V?>8.0 | =$GeneticEvidence1Tally?> 8 |
=PrintWrapperPmid("GeneticEvidence1", $GeneticEvidence1Pmid) ?>
Winkelmann J et al. 2012 May 15 (PMID:22328086); Kernohan KD et al. 2016 Sep 5 (PMID:27602171); Klein CJ et al. 2011 Jun (PMID:21532572); Yuan J et al. 2013 Mar (PMID:23521649); Klein CJ et al. 2013 Feb 26 (PMID:23365052);
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Autosomal Recessive Disease | Two variants in trans and at least one de novo or a predicted/proven null variant | 2 | 0-3 | 12 | =$GeneticEvidence4Vb?> | =$GeneticEvidence4Vb?> | =PrintWrapperPmid("GeneticEvidence4", $GeneticEvidence4Pmid) ?> | |||||
Two variants (not predicted/proven null) with some evidence of gene impact in trans | 1 | 0-1.5 | ||||||||||
Segregation Evidence | Evidence of segregation in one or more families | LOD Score Examples | 3 | 5 | 0-7 | 7 | =$GeneticEvidence5V?>5.0 | =$GeneticEvidence5Tally?>5 | =PrintWrapperPmid("GeneticEvidence5", $GeneticEvidence5Pmid) ?>
Klein CJ et al. 2011 Jun (PMID:21532572);
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2 | 4 | |||||||||||
1.5 | 3 | |||||||||||
1 | 1.5 | |||||||||||
Case-Control Data
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Case-Control Study Type | Case-Control Quality Criteria | Guidelines | Scores | PMIDs/Notes | |||||||
Points/Study | Max | Points | Tally | |||||||||
Single Variant Analysis | 1. Variant Detection Methodology 2. Power 3. Bias and confounding 4. Statistical Significance |
0-6 | 12 | =$GeneticEvidence6V?> | =$GeneticEvidence6Tally?> | =PrintWrapperPmid("GeneticEvidence6", $GeneticEvidence6Pmid) ?> | ||||||
Aggregate Variant Analysis | 0-6 | 12 | =$GeneticEvidence7V?> | =$GeneticEvidence7Tally?> | =PrintWrapperPmid("GeneticEvidence7", $GeneticEvidence7Pmid) ?> | |||||||
Total Genetic Evidence Points (Maximum 12) | =$GeneticEvidenceTotal?>12 |
=$GeneticEvidence8N ?>
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Experimental Evidence
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Evidence Category | Evidence Type | Guidelines | Scores | PMIDs/Notes | |||||||
Default | Range | Max | Points | Tally | ||||||||
Function | Biochemical Function | 0.5 | 0 - 2 | 2 | =$ExperimentalEvidence1V?>2.0 | =$ExperimentalEvidence1Tally?>2 | =PrintWrapperPmid("ExperimentalEvidence1", $ExperimentalEvidence1Pmid) ?>
Klein CJ et al. 2011 Jun (PMID:21532572); |
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Protein Interaction | 0.5 | 0 - 2 | ||||||||||
Expression | 0.5 | 0 - 2 | ||||||||||
Functional Alteration | Patient cells | 1 | 0 - 2 | 2 | =$ExperimentalEvidence2V?>3.0 | =$ExperimentalEvidence2Tally?>2 | =PrintWrapperPmid("ExperimentalEvidence2", $ExperimentalEvidence2Pmid) ?>
Kernohan KD et al. 2016 Sep 5 (PMID:27602171); Klein CJ et al. 2011 Jun (PMID:21532572); Sun Z et al. 2014 Aug (PMID:25033457);
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Non-patient cells | 0.5 | 0 - 1 | ||||||||||
Models & Rescue | Animal model | 2 | 0 - 4 | 4 | =$ExperimentalEvidence3V?> | =$ExperimentalEvidence3Tally?> | =PrintWrapperPmid("ExperimentalEvidence3", $ExperimentalEvidence3Pmid) ?> | |||||
Cell culture model system | 1 | 0 - 2 | ||||||||||
Rescue in animal model | 2 | 0 - 4 | ||||||||||
Rescue in engineered equivalent | 1 | 0 - 2 | ||||||||||
Total Experimental Evidence Points (Maximum 6) | =$ExperimentalEvidenceTotal?>4 |
=$ExperimentalEvidence4N?>
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Assertion criteria | Genetic Evidence (0-12 points) | Experimental Evidence (0-6 points) |
Total Points (0-18) |
Replication Over Time (Y/N) | ||
Description | Case-level, family segregation, or case-control data that support the gene-disease association | Gene-level experimental evidence that support the gene-disease association | Sum of Genetic & Experimental Evidence |
> 2 pubs w/ convincing evidence over time (>3 yrs) | ||
Assigned Points | =$GeneticEvidencePointsTotal?>12 | =$ExperimentalEvidencePointsTotal?>4 | =$EvidencePointsTotal?>16 | =($ReplicationOverTimeYN == 'YES') ? "YES" : "NO"; ?>YES | ||
CALCULATED CLASSIFICATION | LIMITED | 1-6 | ||||
MODERATE | 7-11 | |||||
STRONG | 12-18 | |||||
DEFINITIVE | 12-18 AND replication over time | |||||
Valid contradictory evidence (Y/N)* |
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CALCULATED CLASSIFICATION (DATE) |
=$CalculatedClassification?>
DEFINITIVE
=$CalculatedClassificationDate?>
10/14/2016
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EXPERT CURATION (DATE) |
=$FinalClassification?>
DEFINITIVE
=$FinalClassificationDate?>
02/10/2017
=$FinalClassificationNotes?>
Clinical features of DNMT1 methylopathy include cerebellar ataxia, deafness, and narcolepsy. Reviewed by the ClinGen Hearing Loss Working Group
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