Submissions for variant NM_001482.3(GATM):c.1041C>T (p.Asp347=)

gnomAD frequency: 0.00007  dbSNP: rs139599307

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	RCV000276207	SCV005619894	benign	Arginine:glycine amidinotransferase deficiency	2024-08-20	reviewed by expert panel	curation	The NM_001482.3:c.1041C>T variant in GATM is a synonymous (silent) variant (p.Asp347=). SpliceAI does not predict an impact on splicing, but BP7 was not applied because the nucleotide is conserved (GERP score > 5). To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00101 (31/30616 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). There is a ClinVar entry for this variant (Variation ID: 137450). 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. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on August 20, 2024).
GeneDx	RCV000125210	SCV000168651	benign	not specified	2013-05-29	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.
Illumina Laboratory Services, Illumina	RCV000276207	SCV000391426	uncertain significance	Arginine:glycine amidinotransferase deficiency	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000276207	SCV000646405	likely benign	Arginine:glycine amidinotransferase deficiency	2025-01-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002316370	SCV000851320	likely benign	Inborn genetic diseases	2016-10-19	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.