Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

DNMT1 : DNMT1 Methylopathy

HGNC:2976 | OrphaNet: ORPHA314404 | OMIM:604121
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Genetic Evidence
Case-Level Data
 Evidence Type Case Information Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Variant Evidence
 Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
5.0
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);
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);
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);
2 4
1.5 3
1 1.5
   
Case-Control Data
 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
 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);
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);
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)*
CALCULATED CLASSIFICATION (DATE)
DEFINITIVE
10/14/2016
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