Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

GNMT : glycine N-methyltransferase deficiency

HGNC:4415 | MONDO_0011698
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
1.75
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 3
1.75
Augoustides-Savvopoulou P et al. 2003 (PMID:14739680); Mudd SH et al. 2001 Aug (PMID:11596649); Barić I et al. 2016 May 21 (PMID:27207470);
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) 1.75
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
0.5
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Avila MA et al. 2000 Dec (PMID:11131452);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 2 4.5 4
Liu SP et al. 2007 Nov (PMID:17937387); Luka Z et al. 2006 Jun (PMID:16779654);
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) 4.5

 


 

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 1.75 4.5 6.25 NO
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)
Moderate
06/05/2019
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Limited
06/05/2019
REASON(S) FOR CHANGE
Despite the points technically placing this curation into the Moderate category, the amount of information gathered about this disorder is too small to uphold this classification. With more evidence, particularly genetic, this could be reconsidered.
EXPERT CURATION (DATE)
Limited
05/10/2019
EVIDENCE SUMMARY
The relationship between GNMT and Glycine N-methyltransferase Deficiency (AR) was evaluated using the ClinGen Clinical Validity Framework as of 03/29/19. Variants in GNMT were first reported in humans with this disease as early as 2001 (Mudd et al., PMID: 11596649). At least four variants, mostly missense, have been reported in humans in three publications (Mudd et al., 2001; PMID: 11596649; Barić et al., 2016; PMID: 27207470; Augoustides-Savvopoulou et al., 2003; PMID: 14739680). Patients with GNMT deficiency have elevated serum transaminases without other serious clinical symptoms. Evidence supporting this gene-disease relationship includes case-level data and experimental data, including animal models and expression studies. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Aminoacidopathy Working Group on 05/10/19 (SOP Version 6).