GAMT

guanidinoacetate N-methyltransferase, the group of 7BS small molecule methyltransferases

Basic information

Region (hg38): 19:1397025-1401570

Links

ENSG00000130005 ∙ NCBI:2593 ∙ OMIM:601240 ∙ HGNC:4136 ∙ Uniprot:Q14353 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• guanidinoacetate methyltransferase deficiency (Definitive), mode of inheritance: AR
• guanidinoacetate methyltransferase deficiency (Strong), mode of inheritance: AR
• guanidinoacetate methyltransferase deficiency (Definitive), mode of inheritance: AR
• guanidinoacetate methyltransferase deficiency (Supportive), mode of inheritance: AR
• guanidinoacetate methyltransferase deficiency (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cerebral creatine deficiency syndrome 2 (Guanidinoacetate methyltransferase deficiency)	AR	Biochemical	The condition involves neurologic sequelae, and medical (eg, with creatine-monohydrate, L-ornithine, and/or sodium benzoate) as well as dietary (eg, with ornithine supplementation and protein/arginine restriction) has been reported to increase cerebral creatine, resulting in improvement or stabilization of clinical manifestations in all symptomatic individuals	Biochemical; Neurologic	7808840; 8651275; 9386672; 11196109; 15651030; 17171576; 17336114; 19027335; 20301745; 23031365; 24268530; 34389248

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GAMT gene.

• Cerebral creatine deficiency syndrome (465 variants)
• Deficiency of guanidinoacetate methyltransferase (202 variants)
• not provided (118 variants)
• Inborn genetic diseases (61 variants)
• not specified (58 variants)
• Leigh syndrome (6 variants)
• Mitochondrial complex I deficiency (6 variants)
• GAMT-related condition (2 variants)
• Intellectual disability (2 variants)
• See cases (1 variants)
• Seizure;Intellectual disability (1 variants)
• Abnormality of the nervous system (1 variants)
• Guanidinoacetate methyltransferase (GAMT) deficiency (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GAMT gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			5	122	2	129
missense	5	20	187	3	3	218
nonsense	14	8	2			24
start loss	2					2
frameshift	25	14	2			41
inframe indel	1	1	5			7
splice donor/acceptor (+/-2bp)	2	9	1			12
splice region	1		12	18	1	32
non coding			9	58	16	83
Total	49	52	211	183	21

Highest pathogenic variant AF is 0.000164

Variants in GAMT

This is a list of pathogenic ClinVar variants found in the GAMT region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
19-1397048-G-C		Leigh syndrome • Deficiency of guanidinoacetate methyltransferase • Mitochondrial complex I deficiency	Benign/Likely benign (Jun 19, 2018)
19-1397067-G-A		Deficiency of guanidinoacetate methyltransferase	Uncertain significance (Jan 13, 2018)
19-1397083-G-A		Mitochondrial complex I deficiency • Deficiency of guanidinoacetate methyltransferase • Leigh syndrome	Benign/Likely benign (Jun 19, 2018)
19-1397120-G-A		Deficiency of guanidinoacetate methyltransferase	Uncertain significance (Jan 12, 2018)
19-1397208-A-G		Mitochondrial complex I deficiency • Leigh syndrome • Deficiency of guanidinoacetate methyltransferase	Benign/Likely benign (Jun 14, 2018)
19-1397213-T-G		Mitochondrial complex I deficiency • Deficiency of guanidinoacetate methyltransferase • Leigh syndrome	Benign/Likely benign (Jun 14, 2018)
19-1397223-G-T		Deficiency of guanidinoacetate methyltransferase	Likely benign (Jan 13, 2018)
19-1397243-G-A		Deficiency of guanidinoacetate methyltransferase	Uncertain significance (Jan 12, 2018)
19-1397270-G-T		Deficiency of guanidinoacetate methyltransferase	Likely benign (Jul 26, 2018)
19-1397290-C-T		Deficiency of guanidinoacetate methyltransferase	Uncertain significance (Jan 12, 2018)
19-1397342-C-T		not specified	Likely benign (Oct 07, 2015)
19-1397348-G-A		not specified • Deficiency of guanidinoacetate methyltransferase	Benign (Jun 06, 2022)
19-1397357-G-C			Likely benign (Jan 25, 2019)
19-1397363-C-G		Cerebral creatine deficiency syndrome • Deficiency of guanidinoacetate methyltransferase • Inborn genetic diseases	Uncertain significance (Jun 06, 2022)
19-1397365-T-A		Cerebral creatine deficiency syndrome • Inborn genetic diseases	Conflicting classifications of pathogenicity (Feb 05, 2024)
19-1397368-G-A		Deficiency of guanidinoacetate methyltransferase	Uncertain significance (Sep 04, 2020)
19-1397369-G-A		Cerebral creatine deficiency syndrome • Deficiency of guanidinoacetate methyltransferase	Uncertain significance (Jun 06, 2022)
19-1397373-C-T		Cerebral creatine deficiency syndrome	Uncertain significance (Oct 25, 2021)
19-1397377-G-A		Cerebral creatine deficiency syndrome	Likely benign (Nov 17, 2023)
19-1397378-G-A		Cerebral creatine deficiency syndrome	Uncertain significance (Dec 19, 2021)
19-1397380-C-A		Cerebral creatine deficiency syndrome	Likely benign (Sep 03, 2023)
19-1397380-C-T		Cerebral creatine deficiency syndrome	Likely benign (Jan 09, 2024)
19-1397381-G-A		Cerebral creatine deficiency syndrome • Deficiency of guanidinoacetate methyltransferase	Uncertain significance (Jun 06, 2022)
19-1397392-T-C		Cerebral creatine deficiency syndrome	Likely benign (Jan 30, 2024)
19-1397393-G-A		Deficiency of guanidinoacetate methyltransferase	Uncertain significance (Jun 06, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GAMT	protein_coding	protein_coding	ENST00000447102	5	4479

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00948	0.828	125517	0	8	125525	0.0000319

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.0872	153	150	1.02	0.00000858	1699
Missense in Polyphen		46	46.021	0.99954		506
Synonymous	0.0246	64	64.3	0.996	0.00000399	550
Loss of Function	1.11	4	7.24	0.553	3.11e-7	84

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000134	0.000123
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.0000363	0.0000353
Middle Eastern	0.0000544	0.0000544
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Converts guanidinoacetate to creatine, using S- adenosylmethionine as the methyl donor (PubMed:26003046, PubMed:24415674, PubMed:26319512). Important in nervous system development (PubMed:24415674). {ECO:0000269|PubMed:24415674, ECO:0000269|PubMed:26003046, ECO:0000269|PubMed:26319512}.
• Pathway: Arginine and proline metabolism - Homo sapiens (human);Glycine, serine and threonine metabolism - Homo sapiens (human);3-Phosphoglycerate dehydrogenase deficiency;Hyperornithinemia with gyrate atrophy (HOGA);Creatine deficiency, guanidinoacetate methyltransferase deficiency;L-arginine:glycine amidinotransferase deficiency;Hyperornithinemia-hyperammonemia-homocitrullinuria [HHH-syndrome];Guanidinoacetate Methyltransferase Deficiency (GAMT Deficiency);Non Ketotic Hyperglycinemia;Glycine and Serine Metabolism;Dimethylglycine Dehydrogenase Deficiency;Hyperglycinemia, non-ketotic;Prolinemia Type II;Prolidase Deficiency (PD);Arginine and Proline Metabolism;Dimethylglycine Dehydrogenase Deficiency;Sarcosinemia;Hyperprolinemia Type I;Hyperprolinemia Type II;Ornithine Aminotransferase Deficiency (OAT Deficiency);Arginine: Glycine Amidinotransferase Deficiency (AGAT Deficiency);Dihydropyrimidine Dehydrogenase Deficiency (DHPD);MECP2 and Associated Rett Syndrome;Urea cycle and metabolism of amino groups;Metabolism of polyamines;Metabolism of amino acids and derivatives;Glycine Serine metabolism;Metabolism;Arginine Proline metabolism;creatine biosynthesis;Creatine metabolism (Consensus)

Recessive Scores

• pRec: 0.189

Intolerance Scores

• loftool: 0.140
• rvis_EVS: -0.09
• rvis_percentile_EVS: 46.74

Haploinsufficiency Scores

• pHI: 0.0969
• hipred: N
• hipred_score: 0.170
• ghis: 0.520

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.955

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Gamt
• Phenotype: behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); reproductive system phenotype; homeostasis/metabolism phenotype; renal/urinary system phenotype; growth/size/body region phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); endocrine/exocrine gland phenotype; cellular phenotype

Gene ontology

• Biological process: creatine metabolic process;creatine biosynthetic process;muscle contraction;spermatogenesis;animal organ morphogenesis;methylation;regulation of multicellular organism growth;S-adenosylhomocysteine metabolic process;S-adenosylmethionine metabolic process
• Cellular component: nucleus;cytoplasm;cytosol
• Molecular function: methyltransferase activity;S-adenosylmethionine-dependent methyltransferase activity;guanidinoacetate N-methyltransferase activity