Submissions for variant NM_001482.3(GATM):c.1237C>T (p.Arg413Trp)

dbSNP: rs1244824806

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV001779072	SCV002600071	likely pathogenic	Arginine:glycine amidinotransferase deficiency	2024-08-20	reviewed by expert panel	curation	The NM_001482.3:c.1237C>T variant in GATM is a missense variant predicted to cause the substitution of an arginine by a tryptophan at amino acid position 413 (p.Arg413Trp). This variant has been detected in one individual with AGAT deficiency who had low guanidinoacetate in plasma and low to low-normal creatine in plasma, as well as significantly decreased creatine peak on brain MRS (PMID 26490222) (PP4_Strong). This individual was compound heterozygous for the variant and a likely pathogenic variant (p.Arg413Gln, ClinVar ID: 2446451), and the variants were confirmed in trans by parental testing (PMID 23660394) (PM3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Expression of the variant in HeLa cells resulted in 0% wild type AGAT activity (PMID: 27233232), indicating that this variant may impact protein function (PS3_Supporting). The computational predictor REVEL gives a score of 0.585 which is neither above nor below the thresholds predicting a damaging (>0.75) or benign (<0.15) impact on AGAT function.Another missense variant c.1238G>A, (p.Arg413Gln) (PMID: 23660394, 26490222, 27233232) in the same codon has been classified as likely pathogenic for AGAT deficiency by the ClinGen CCDS VCEP (ClinVar ID: 2446451) (PM5_Supporting). There is a ClinVar entry for this variant (Variation ID: 598112). In summary, this variant meets the criteria to be classified as likely pathogenic 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): PP4_Strong, PM3, PM2_Supporting, PS3_Supporting, PM5_Supporting. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on August 20, 2024).
Eurofins Ntd Llc (ga)	RCV000734428	SCV000862570	uncertain significance	not provided	2018-08-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001779072	SCV002015016	likely pathogenic	Arginine:glycine amidinotransferase deficiency	2021-10-22	criteria provided, single submitter	clinical testing	Variant summary: GATM c.1237C>T (p.Arg413Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250540 control chromosomes (gnomAD). c.1237C>T has been reported in the literature in a compound heterozygous individual affected with Arginine:glycine Amidinotransferase Deficiency (Comeaux_2013). Experimental evidence evaluating an impact on protein function demonstrated the variant retained 0% of wild-type GATM activity (DesRoches_2016). A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001779072	SCV002131603	uncertain significance	Arginine:glycine amidinotransferase deficiency	2024-07-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 413 of the GATM protein (p.Arg413Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cerebral creatine deficiency syndrome (PMID: 26490222). ClinVar contains an entry for this variant (Variation ID: 598112). 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 expected to disrupt GATM protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GATM function (PMID: 27233232). This variant disrupts the p.Arg413 amino acid residue in GATM. Other variant(s) that disrupt this residue have been observed in individuals with GATM-related conditions (PMID: 26490222), which suggests that this may be a clinically significant amino acid residue. 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.