Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

MMACHC : methylmalonic aciduria and homocystinuria type cblC

HGNC:24525 | MONDO_0010184
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Aminoacidopathy
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
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
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 16
12
12
Lerner-Ellis JP et al. 2006 Jan (PMID:16311595); Hu S et al. 2018 Aug 29 (PMID:30157807); Yuen YP et al. 2007 Jan (PMID:16963011); Nogueira C et al. 2008 Apr (PMID:18164228); Almannai M et al. 2017 Sep (PMID:28693988); Zong Y et al. 2015 Jul 7 (PMID:26149271);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 3
1.2
Hu S et al. 2018 Aug 29 (PMID:30157807); Backe PH et al. 2013 Apr 12 (PMID:23580368);
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 1
0.5
0.5
Kim J et al. 2008 Sep 23 (PMID:18779575);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
0.5
Non-patient cells 0.5 0 - 1 1 0.5
Froese DS et al. 2009 Dec (PMID:19700356);
Models Non-human model organism 2 0 - 4 4 1 1 2
Moreno-Garcia MA et al. 2014 Jul (PMID:24889031);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2 1 1
Lerner-Ellis JP et al. 2006 Jan (PMID:16311595);
Total Experimental Evidence Points (Maximum 6) 3

 


 

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 3 15 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
05/10/2019
EXPERT CURATION (DATE)
Definitive
05/24/2019
EVIDENCE SUMMARY
MMACHC was first reported in relation to autosomal recessive inheritance of methylmalonic aciduria and homocystinuria type cblC in 2007 (Lerner-Ellis et al. PMID: 16311595). At least 93 unique variants (including many missense, nonsense, and small deletions or insertions, as well as some splicing variants) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 19 probands in 7 publications (PMIDs: 26149271, 28693988, 18164228, 16963011, 30157807, 16311595, 23580368). More evidence is available in the literature, but the maximum score for genetic evidence has been reached. This gene-disease relationship is supported by experimental evidence of the biochemical function, functional alteration in non-patient cells, rescue in patient cells, and a mouse model (PMIDs: 18779575, 19700356, 24889031, 16311595) . In summary, MMACHC is definitively associated with autosomal recessive inheritance of methylmalonic aciduria and homocystinuria type cblC. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.