Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

MUT : methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency

HGNC:7526 | MONDO_0009612
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 8
Chu J et al. 2016 Aug (PMID:27233228); Han LS et al. 2015 Nov (PMID:26454439); Acquaviva C et al. 2005 Feb (PMID:15643616);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 6
Chu J et al. 2016 Aug (PMID:27233228); Keyfi F et al. 2016 Jan 15 (PMID:26449400); Han LS et al. 2015 Nov (PMID:26454439); Ledley FD et al. 1990 Apr (PMID:1970180); Acquaviva C et al. 2005 Feb (PMID:15643616);
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
Goodey PA et al. 1972 Nov (PMID:4654847);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1 1 0.5
Forny P et al. 2014 Dec (PMID:25125334);
Models Non-human model organism 2 0 - 4 4 1 3 4
Forny P et al. 2016 Sep 23 (PMID:27519416);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 1
Carrillo-Carrasco N et al. 2010 Sep (PMID:20486773);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 5.5



Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
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
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 5.5 17.5 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
The relationship between MUT and methylmalonic academi¬a due to methylmalonyl-CoA deficiency, an autosomal recessive disorder of propionyl-CoA metabolism, was evaluated using the ClinGen Clinical Validity Framework as of April 25th, 2019. Methlmalonyl-CoA mutase (MCM) is a mitochondrial enzyme that catalyzes the isomerization of L-methylmalonyl-CoA to succinyl-CoA using cobalamin as a cofactor. This is a key reaction in propionyl-CoA metabolism. Variants in MCM cause the mut type of methylmalonic aciduria, including mut0 (complete deficiency) and mut- (partical deficiency). Variants in MUT causing MMA were first reported by Ledley et al in 1990 (PMID 1970180). Since then, over 250 MUT variants have been reported. Data from 14 patients with 18 unique variants (missense, nonsense, frameshift, and splicing) from 5 publications were curated (Ledley et al, 1990, PMID 1970180; Acquaviva et al, 2005, PMID 15643616; Han et al, 2015, PMID 26454439; Chu et al, 2016, PMID 27233228; Keyfi et al, 2016, PMID 26449400). This gene-disease relationship is supported by the biochemical function of methylmalonyl-CoA mutase (Goodey et al, 1972, PMID 4654847), which is consistent with the elevated MMA and propionyl carnitine observed in patients with this condition; functional studies (Forney et al, 2014; PMID 25125334); mouse models (including Forney et al, PMID 27519416) and the results of gene therapy in a knockout mouse (Carrillo-Carrasco et al, 2010, PMID 20486773). This curation and includes data provided by Counsyl. In summary, MUT is definitively associated with autosomal recessive methylmalonic aciduria. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This curation included data collected by Counsyl. The classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel on May 9th, 2019.