Submissions for variant NM_001482.3(GATM):c.407C>T (p.Thr136Met)

gnomAD frequency: 0.00063  dbSNP: rs148564534

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV001082642	SCV003852690	benign	Arginine:glycine amidinotransferase deficiency	2023-01-25	reviewed by expert panel	curation	The NM_001482.3:c.407C>T variant in GATM is a missense variant predicted to cause substitution of threonine by methionine at amino acid 136 (p.Thr136Met). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0007357 (95/129130 alleles) in the non-Finnish European 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 >50% wild type AGAT activity suggesting that this variant does not significantly impact protein function (PMID: 27233232) (BS3_Supporting). The computational predictor REVEL gives a score of 0.049 which is below the threshold of 0.15, evidence that does not predict a damaging effect on AGAT function (BP4). There is a ClinVar entry for this variant (Variation ID: 205613). 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 1.0): BA1, BS3_Supporting, BP4. (Classification approved by the ClinGen CCDS VCEP on January 25, 2023).
GeneDx	RCV000437121	SCV000241193	likely benign	not provided	2020-08-28	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27233232)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000437121	SCV000511235	uncertain significance	not provided	2017-01-09	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082642	SCV000646410	benign	Arginine:glycine amidinotransferase deficiency	2024-01-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002317103	SCV000850349	benign	Inborn genetic diseases	2016-06-07	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.
Athena Diagnostics	RCV000437121	SCV001143988	likely benign	not provided	2018-10-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001082642	SCV001280440	uncertain significance	Arginine:glycine amidinotransferase deficiency	2018-01-13	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.
CeGaT Center for Human Genetics Tuebingen	RCV000437121	SCV004698925	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	GATM: BP4, BS2
Hospital for Sick Children	RCV000437121	SCV000267662	not provided	not provided		no assertion provided	in vitro
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001251999	SCV001427745	likely benign	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing