Submissions for variant NM_001482.3(GATM):c.1244G>A (p.Arg415Gln)

gnomAD frequency: 0.00004  dbSNP: rs374592247

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV000809560	SCV002600069	benign	Arginine:glycine amidinotransferase deficiency	2022-06-06	reviewed by expert panel	curation	The NM_001482.3:c.1244G>A variant in GATM is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 415 (p.Arg415Gln). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000915 (28/30616 alleles) in the South Asian population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.0005), and therefore meets this criterion (BA1). Expression of the variant in HeLa cells resulted in 39% wild type AGAT activity suggesting that this variant does not significantly impact protein function (PMIDS)(BS3_Supporting). The computational predictor REVEL gives a score of 0.201 which is neither above nor below the thresholds predicting a damaging (>0.75) or benign (<0.15) impact on AGAT function. There is a ClinVar entry for this variant (Variation ID: 225921). In summary, this variant meets the criteria to be classified as benign for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): BA1, BS3_Supporting. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000809560	SCV000949714	uncertain significance	Arginine:glycine amidinotransferase deficiency	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 415 of the GATM protein (p.Arg415Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with GATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 225921). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GATM protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect GATM function (PMID: 27233232). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000488907	SCV001777351	uncertain significance	not provided	2024-06-03	criteria provided, single submitter	clinical testing	Published functional studies demonstrate no damaging effect (PMID: 27233232); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27233232)
Fulgent Genetics, Fulgent Genetics	RCV002494554	SCV002777092	uncertain significance	Arginine:glycine amidinotransferase deficiency; Fanconi renotubular syndrome 1	2022-03-01	criteria provided, single submitter	clinical testing
Hospital for Sick Children	RCV000488907	SCV000267672	not provided	not provided		no assertion provided	in vitro