Submissions for variant NM_000156.6(GAMT):c.626C>T (p.Thr209Met)

gnomAD frequency: 0.07010  dbSNP: rs17851582

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV000020144	SCV002600139	benign	Deficiency of guanidinoacetate methyltransferase	2022-06-06	reviewed by expert panel	curation	The NM_000156.6:c.626C>T variant in GAMT is a missense variant predicted to result in the substitution of threonine for methionine at amino acid 209 (p.Thr209Met). The highest continental population minor allele frequency in gnomAD v2.1.1 is 0.09656 (12354/ 127944 alleles) in the European non-Finnish population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.003), and therefore meets this criterion (BA1). There are 987 homozygotes in gnomAD v2.1.1. Given that GAMT deficiency has an early onset, this data supports that the variant does not cause the condition (BS2). The computational predictor REVEL gives a score of 0.313 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAMT function (BP4). It has been previously reported in a large Italian family (PMID: 12468279), where it did not segregate with AGAT deficiency, including being found in the homozygous state in the father, who was asymptomatic and had normal GAMT enzyme activity. It has also been found in presumed cis with the c.160G>C (p.Ala54Pro) variant in a patient with severe GAMT deficiency, as both parents were heterozygous for both the c.160G>C variant and c.626C>T variant and the patient was homozygous for both variants (PMID: 15108290). In this publication (PMID: 15108290), the c.626C>T was classified as a benign polymorphism due to its high frequency in a group of control individuals screened. It is noted in ClinVar (Variation ID: 21068). In summary, this variant meets the criteria to be classified as benign for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 1.1.0): BA1, BS2, BP4. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).
GeneDx	RCV000117117	SCV000168636	benign	not specified	2013-05-28	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.
PreventionGenetics, part of Exact Sciences	RCV000117117	SCV000302738	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000020144	SCV000483720	benign	Deficiency of guanidinoacetate methyltransferase	2018-03-06	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000272863	SCV000483721	likely benign	Leigh syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000311501	SCV000483722	likely benign	Mitochondrial complex I deficiency	2016-06-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002311515	SCV000846232	benign	Inborn genetic diseases	2017-02-10	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000020144	SCV000883934	benign	Deficiency of guanidinoacetate methyltransferase	2021-06-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000117117	SCV000919413	benign	not specified	2018-11-09	criteria provided, single submitter	clinical testing	Variant summary: GAMT c.626C>T (p.Thr209Met) 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 allele was found at a frequency of 0.076 in 273748 control chromosomes in the gnomAD database, including 972 homozygotes. The observed variant frequency is approximately 70 fold of the estimated maximal expected allele frequency for a pathogenic variant in GAMT causing Guanidinoactetate methyltransferase deficiency phenotype (0.0011), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.626C>T in individuals affected with Guanidinoactetate methyltransferase deficiency has been reported. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Battini 2002). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both laboratories classified the variant as benign (1x)/likely benign(1x). Based on the evidence outlined above, the variant was classified as likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001520666	SCV001729827	benign	Cerebral creatine deficiency syndrome	2025-02-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000020144	SCV001761400	benign	Deficiency of guanidinoacetate methyltransferase	2021-07-10	criteria provided, single submitter	clinical testing
Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	RCV000117117	SCV005091824	benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing	This variant is classified as Benign based on local population frequency. This variant was detected in 20% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 19. Only high quality variants are reported.
Breakthrough Genomics, Breakthrough Genomics	RCV000676877	SCV005208817	likely benign	not provided		criteria provided, single submitter	not provided
GeneReviews	RCV000020144	SCV000040471	not provided	Deficiency of guanidinoacetate methyltransferase		no assertion provided	literature only
Genetic Services Laboratory, University of Chicago	RCV000117117	SCV000151278	likely benign	not specified		no assertion criteria provided	clinical testing	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.
Mayo Clinic Laboratories, Mayo Clinic	RCV000676877	SCV000802691	benign	not provided	2016-02-19	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000020144	SCV001454095	benign	Deficiency of guanidinoacetate methyltransferase	2020-09-16	no assertion criteria provided	clinical testing