Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

GATM : AGAT deficiency

HGNC:4175 | MONDO_0012996
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 7
Item CB et al. 2001 Nov (PMID:11555793); Stockler-Ipsiroglu S et al. 2015 Dec (PMID:26490222); Ndika JD et al. 2012 May (PMID:22386973); Edvardson S et al. 2010 Oct-Nov (PMID:20682460); Verma A et al. 2010 Jul 13 (PMID:20625172); Nouioua S et al. 2013 Aug (PMID:23770102);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
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 3
Borsook H et al. 1940 Jun 7 (PMID:17789505); CANTONI GL et al. 1954 Aug (PMID:13192118); 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 0.5
DesRoches CL et al. 2016 Sep (PMID:27233232);
Models Non-human model organism 2 0 - 4 4 3 2 2
Choe CU et al. 2013 Jan 1 (PMID:23026748); Iqbal F et al. 2017 Dec (PMID:28808834); Nabuurs CI et al. 2013 Jan 15 (PMID:23129796);
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



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 4 16 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
The relationship between GATM and arginine:glycine amidinotransferase (AGAT) deficiency, an autosomal recessive disorder of creatine metabolism, was evaluated using the ClinGen Clinical Validity Framework as of February 6th, 2019. Variants in GATM were first reported in humans with this disorder in 2001 (Item et al, PMID 11555793) in two sisters previously reported with creatine deficiency in the brain (Bianchi et al, 2000; PMID 10762163). Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. At least 7 unique variants (missense, nonsense, frameshift, and splice site) have been reported in 6 probands in 5 publications (Edvardson et al, 2010, PMID 20682460; Verma et al, 2010, PMID 20625172; Ndika et al, 2012, PMID 22386973; Nouioua et al, 2013, PMID 23770102; Stockler-Ipsiroglu et al, 2015, PMID 26490222). Variants in this gene segregated with disease in 3 additional family members in one large family (Battini et al, 2002, PMID 12468279). More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 points) has been reached. The mechanism for disease is biallelic loss of function. This gene-disease relationship is supported by the biochemical function of AGAT, catalyzing the first step of creatine synthesis, functional analysis of missense variants (Des Roches et al, 2016, PMID 27233232), and the biochemical features and clinical features of a null mouse model (Choe et al, 2013, PMID 23026748; Nabuurs et al, 2015, PMID 23129796; Iqbal et al, PMID 28808834). In summary, GATM is definitively associated with AGAT deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Of note, this gene has also been implicated in renal Fanconi syndrome and kidney failure. That gene-disease relationship will be assessed separately.