| Gene/Disease Pair: | DNMT1 : 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 |
5.0
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5 |
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 | |||||||||
| Proband with other variant type with some evidence of gene impact | 0.5 | 0-1.5 | 7 | 8.0 | 8 |
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 | ||||||||
| 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 | 5.0 | 5 |
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 | |||||||||
| Aggregate Variant Analysis | 0-6 | 12 | ||||||||||
| Total Genetic Evidence Points (Maximum 12) | 12 | |||||||||||
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 | 2.0 | 2 |
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 | 3.0 | 2 |
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 | ||||||||
| 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) | 4 | |||||||||||
| 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 | 12 | 4 | 16 | 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) |
DEFINITIVE
10/14/2016
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| EXPERT CURATION (DATE) |
DEFINITIVE
02/10/2017
Clinical features of DNMT1 methylopathy include cerebellar ataxia, deafness, and narcolepsy. Reviewed by the ClinGen Hearing Loss Working Group
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