AMT

protein-coding

aminomethyltransferase, the group of Methyltransferase families

Gene summary

This gene encodes one of four critical components of the glycine cleavage system. Mutations in this gene have been associated with glycine encephalopathy. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

MANE transcript

NM_000481.4

Inheritance

ClinVar variants

P:162U:200B:231

Top phenotype

Glycine encephalopathy 2

gnomAD constraint

pLI —, LoF o/e 0.42

Max pathogenic AF

—

Genomic locus

chr3:49,416,778-49,422,685

External References & Databases

Ensembl (ENSG00000145020)

Transcript & Mutation Effects

hg38 • Region Span ~5.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

glycine encephalopathy 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0958192

Submitter: G2P

glycine encephalopathy 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0958179

Submitter: PanelApp Australia

atypical glycine encephalopathySUPPORTIVE

Inheritance Pattern: Unknown

Disease ID:MONDO:0015010

Submitter: Orphanet

glycine encephalopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011612

Submitter: ClinGen

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.

neonatal glycine encephalopathySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017353

Submitter: Orphanet

infantile glycine encephalopathySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017354

Submitter: Orphanet

glycine encephalopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011612

Submitter: Myriad Women's Health

glycine encephalopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011612

Submitter: Natera

glycine encephalopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011612

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Glycine encephalopathy 2AR

Manifestation: Biochemical; Neurologic; Ophthalmologic

Intervention: Biochemical; Pharmacogenomic

Rationale: There is no current effective treatment for severe disease; however, children with mutations associated with residual GCS enzyme activity treated aggressively early with sodium benzoate and N-methyl D-aspartate receptor site antagonists may have improved outcomes; Valproate should be avoided

Refs: 11139253; 12948742; 16151895; 16450403; 20301531; 19299230; 21470805; 28462797

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AMT variants in ClinVar

9 Conditions Cataloged

Glycine encephalopathyTotal: 683

not providedTotal: 79

Inborn genetic diseasesTotal: 62

Glycine encephalopathy 2Total: 58

Glycine encephalopathy 1Total: 49

not specifiedTotal: 41

AMT-related disorderTotal: 27

Neurodevelopmental delayTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000481.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar	2 clinvar	214 clinvar		217
missense	6 clinvar	39 clinvar	194 clinvar	17 clinvar		256
nonsense	13 clinvar	8 clinvar	1 clinvar			22
start loss	2 clinvar	2 clinvar				4
frameshift	31 clinvar	35 clinvar	2 clinvar			68
splice donor/acceptor (+/-2bp)	7 clinvar	18 clinvar	1 clinvar			26
Total	59	103	200	231	0	593

Highest pathogenic variant AF is 0.00007992783

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 58 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000481.4	RefSeq	NP_000472.2	9	MANE Select
ENST00000273588.9	Ensembl	ENSP00000273588.3	9	MANE Select
NM_001164710.2	RefSeq	NP_001158182.1	8	Standard
NM_001164711.2	RefSeq	NP_001158183.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

One carbon pool by folate - Homo sapiens (human)
Glycine, serine and threonine metabolism - Homo sapiens (human)
Glyoxylate and dicarboxylate metabolism - Homo sapiens (human)
3-Phosphoglycerate dehydrogenase deficiency
Non Ketotic Hyperglycinemia

Biological Process

glycine catabolic process
glycine decarboxylation via glycine cleavage system
methylation

Molecular Function

aminomethyltransferase activity
transaminase activity

Cellular Component

nucleoplasm
mitochondrion
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000273588
Coding exons: 9
Length: 5976
Individuals with no LoFs: 125712
Homozygous LoFs: 0
Heterozygous LoFs: 36
Defined: 125748
p: 0.000143

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.101	244	240	1.02	0.0000149	2610
Missense (PolyPhen)		80	93.425	0.8563		1045
Synonymous	-0.472	101	95.1	1.06	0.00000570	861
Loss of Function	2.19	7	16.7	0.420	8.27e-7	193

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0.00032	0.00032	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.000098	0.000097	rare
South Asian	0.00029	0.00029	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: The glycine cleavage system catalyzes the degradation of glycine. {ECO:0000269|PubMed:16051266}.;
Disease: DISEASE: Non-ketotic hyperglycinemia (NKH) [MIM:605899]: Autosomal recessive disease characterized by accumulation of a large amount of glycine in body fluid and by severe neurological symptoms. {ECO:0000269|PubMed:10873393, ECO:0000269|PubMed:11286506, ECO:0000269|PubMed:16051266, ECO:0000269|PubMed:26371980, ECO:0000269|PubMed:28244183, ECO:0000269|PubMed:8005589, ECO:0000269|PubMed:9600239, ECO:0000269|PubMed:9621520}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.277

Intolerance Scores

LoFtool: 0.0987
RVIS EVS: -0.38
RVIS percentile EVS: 28.01

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0200

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium