Submissions for variant NM_001482.3(GATM):c.669T>C (p.Tyr223=)

gnomAD frequency: 0.00163  dbSNP: rs151231277

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV001084172	SCV003852692	benign	Arginine:glycine amidinotransferase deficiency	2023-01-25	reviewed by expert panel	curation	The NM_001482.3:c.669T>C (p.Tyr223=) variant in GATM is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by PhyloP (BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00501 (125/24958 alleles) in the African population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.0005), and therefore meets this criterion (BA1). The computational splicing predictor SpliceAI gives a score of 0.0 for donor and acceptor loss suggesting that the variant has no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 137449). 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, BP4, BP7. (Classification approved by the ClinGen CCDS VCEP on January 25, 2023).
GeneDx	RCV000125209	SCV000168650	benign	not specified	2013-07-10	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084172	SCV000646414	benign	Arginine:glycine amidinotransferase deficiency	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002312565	SCV000847340	benign	Inborn genetic diseases	2016-06-13	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Eurofins Ntd Llc (ga)	RCV000732171	SCV000860084	uncertain significance	not provided	2018-03-12	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000732171	SCV001978256	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000732171	SCV001980097	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004751275	SCV005344652	benign	GATM-related disorder	2024-04-05	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).