Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

MTHFR : homocystinuria due to methylene tetrahydrofolate reductase deficiency

HGNC:7436 | MONDO_0009353
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 6
11
12
Goyette P et al. 1994 Jun (PMID:7920641); Burda P et al. 2015 Jun (PMID:25736335); Forges T et al. 2010 Jun (PMID:20356773); Tonetti C et al. 2003 Jul (PMID:12733064);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 1
1
Burda P et al. 2015 Jun (PMID:25736335);
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
1
1
Levin BL et al. 2016 Oct (PMID:27130656);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 1
1
1
Burda P et al. 2017 Mar (PMID:27743313);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 2 2
Chen Z et al. 2001 Mar 1 (PMID:11181567);
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
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)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
08/02/2019
EXPERT CURATION (DATE)
Definitive
06/18/2019
EVIDENCE SUMMARY
The relationship between MTHFR and homocystinuria due to methylene tetrahydrofolate reductase deficiency (autosomal recessive) was evaluated using the ClinGen Clinical Validity Framework as of June, 2019. MTHFR encodes methylenetetrahydrofolate reductase which converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cosubstrate for homocysteine remethylation to methionine. Deficiency of MTHFR is associated with elevated homocysteine and decreased methionine, Variants in MTHFR were first reported in humans with this deficiency in 1994 (Goyette et al., PMID 7920641. At least 109 unique variants (missense, nonsense, frameshift, splicing, deletion) have been identified in humans (Froese et al., 2016; PMID 26872964). Evidence supporting this gene-disease relationship includes case-level and experimental data. This gene-disease relationship is supported by biochemical assays, in vitro studies and a mouse model. In summary, MTHFR is definitively associated with autosomal recessive homocystinuria due to methylene tetrahydrofolate reductase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel on 6/18/19 (SOP Version 6). Of note, MTHFR polymorphisms have been associated with susceptibility to neural tube defects, schizophrenia, thromboembolism, and vascular disease. However, at this time, these entities are not included for analysis using the ClinGen Clinical Validity Framework.