Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

AMT : glycine encephalopathy

HGNC:473 | MONDO_0011612
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
Swanson MA et al. 2015 Oct (PMID:26179960); Gencpinar P et al. 2016 Jun 1 (PMID:27164344);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 5
Swanson MA et al. 2015 Oct (PMID:26179960); Azize NA et al. 2014 Nov (PMID:25231368); Belcastro V et al. 2016 Jan (PMID:26371980); Nanao K et al. 1994 Jun (PMID:8005589);
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 2
Fujiwara K et al. 1984 Sep 10 (PMID:6469978); Fujiwara K et al. 1983 Jul 10 (PMID:6863283);
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
Models Non-human model organism 2 0 - 4 4
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) 2



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 2 14 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
The relationship between AMT and glycine encephalopathy, an autosomal recessive disorder of the glycine cleavage system, was evaluated using the ClinGen Clinical Validity Framework as of April 6th, 2019. Variants in AMT, which encodes the T-protein (aminomethyltransferase) of the glycine cleavage system, were first reported in humans with this disease as early as 1994 (Nanao et al, PMID 8005589). Variants in AMT have been reported in over 100 cases of glycine encephalopathy (non-ketotic hyperglycinemia, NKH) and include missense, nonsense, frameshift, and splice site variants. Variants in this gene have been reported in about 15-20% of probands with glycine encephalopathy; about 80% of patients have variants in GLDC which encodes the P-protein of the glycine cleavage system (Coughlin et al, 2017, PMID 27362913). Eleven patients with 15 unique variants in AMT are included here (Nanao et al, 1994, PMID 8005589; Azize et al, 2014, PMID 25231368; Swanson et al, 2015, PMID 26179960; Belcastro et al, 2016, PMID 26371980; Gencpinar et al, 2016, PMID 27164344). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Various recurrent variants have been reported, including p.Arg320His (Coughlin et al, 2017, PMID 27362913). The mechanism for disease is biallelic loss of function. This gene-disease relationship is supported by the biochemical function of the T protein (aminomethyltransferase) in the glycine cleavage system (Fujiwara and Motokara, 1983, PMID 6863283; Kilkuchi et al, 2008, PMID 18941301), and the knowledge that GLDC, encoding the P-protein of the glycine cleavage system, is definitely associated with glycine encephalopathy. In summary, AMT is definitively associated with autosomal recessive glycine encephalopathy. 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 GCEP on May 24th, 2019.