Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

GAMT : guanidinoacetate methyltransferase deficiency

HGNC:4136 | MONDO_0012999
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 8
Stöckler S et al. 1996 May (PMID:8651275); Carducci C et al. 2000 Dec (PMID:11136556); Schulze A et al. 2003 Feb (PMID:12557293); Item CB et al. 2004 May (PMID:15108290); Leuzzi V et al. 2006 Jan (PMID:16293431);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 2
Item CB et al. 2004 May (PMID:15108290); Verbruggen KT et al. 2007 Jul (PMID:17466557);
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 4
Schulze A et al. 2003 Feb (PMID:12701824); CANTONI GL et al. 1954 Aug (PMID:13192118); Borsook H et al. 1940 Jun 7 (PMID:17789505); Guimbal C et al. 1993 Apr 25 (PMID:8473283);
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 1 1
Mercimek-Mahmutoglu S et al. 2014 Apr (PMID:24415674);
Models Non-human model organism 2 0 - 4 4 2 2.5 3.5
Schmidt A et al. 2004 May 1 (PMID:15028668); Iqbal F et al. 2017 Dec (PMID:28808834);
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 1 1
Almeida LS et al. 2006 Dec (PMID:16899382);
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 6



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 6 18 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
GAMT was first reported in relation to GAMT deficiency in 1994 (Stöckler et al, PMID 7808840; Stöckler et al, 1996, PMID 8651275). GAMT deficiency is inherited in an autosomal recessive manner. At least 120 cases have been reported worldwide (Mercimek-Mahmatoglu and Salomons, 2009, PMID 20301745). Evidence supporting this gene-disease relationship includes case-level and experimental data. Eleven unique variants (nonsense, frameshift, splice site, and missense) in 9 probands were curated (Stöckler et al, 1996, PMID 8651275; Carducci et al, 2000, PMID 11136556; Schulze, 2003, PMID 12557293; Item et al, 2004, PMID 15108290; Leuzzi et al, 2006, PMID 16293431; Verbruggen et al, 2007, PMID 17466557). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Of note, common variants include p.Trp20Ser (c.59G>C) and c.327G>A (impacting splicing by altering the last nucleotide of exon 2) (Mercimek-Mahmatoglu and Salomons, 2009, PMID 20301745). The mechanism for disease is biallelic loss of function. This gene-disease association is supported by the function of GAMT in creatine synthesis (see Schulze, 2003, PMID 12701824 for review), functional analysis of missense variation in GAMT (Mercimek-Mahmatoglu et al, 2014, PMID 2441567), rescue of GAMT activity by expression of the cDNA in cultured fibroblasts from a patient with GAMT deficiency (Almeida et al, 2006, PMID 16899382), and the biochemical features and impact of creatine supplementation in a GAMT knockout mouse model (Schmidt et al, 2004, 15028668; Iqbal et al, 2018, PMID 28808834). More experimental evidence may be available but the maximum score (6 points) has been reached. In summary, GAMT is definitively associated with GAMT 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 Aminoacidopathies GCEP on January 25th, 2019.