Submissions for variant NM_000156.6(GAMT):c.79T>C (p.Tyr27His)

gnomAD frequency: 0.00345  dbSNP: rs200833152

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV001127426	SCV003852727	benign	Deficiency of guanidinoacetate methyltransferase	2023-02-08	reviewed by expert panel	curation	NM_000156.6:c.79T>C variant in GAMT is a missense variant that is predicted to result in the substitution of tyrosine by histidine at amino acid 27 (p.Tyr27His). This variant was identified in the homozygous state in an individual with normal GAMT enzyme activity in fibroblasts (PMID: 24415674). The variant is present in gnomAD v2.1.1. at a maximum population frequency of 0.00471 (>0.003, cutoff for BA1) and found in the homozygous state in 2 individuals in gnomAD v2.1.1 (BA1). In fibroblasts, overexpressing the GAMT c.79T>C (p.Tyr27His) variant, restored GAMT activity to similar levels as the wild-type GAMT transfection (PMID: 24415674)(BS3_Supporting). There is a ClinVar entry for this variant (Variation ID: 167131). In summary, this variant meets the criteria to be classified as benign for GAMT deficiency. GAMT-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Cerebral Creatine Deficiencies VCEP (Specifications Version 1.1.0): BA1, BS3_Supporting. (Classification approved by the ClinGen CCDS VCEP on February 8, 2023).
Eurofins Ntd Llc (ga)	RCV000153308	SCV000202787	benign	not specified	2017-02-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000153308	SCV000241179	benign	not specified	2018-02-15	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.
Genetic Services Laboratory, University of Chicago	RCV000153308	SCV000247450	uncertain significance	not specified	2014-09-16	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224880	SCV000281130	uncertain significance	not provided	2016-04-29	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081204	SCV000562805	benign	Cerebral creatine deficiency syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002312992	SCV000849302	likely benign	Inborn genetic diseases	2018-11-03	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.
Athena Diagnostics	RCV000224880	SCV001143982	benign	not provided	2019-03-19	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001127426	SCV001286738	uncertain significance	Deficiency of guanidinoacetate methyltransferase	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CeGaT Center for Human Genetics Tuebingen	RCV000224880	SCV001501211	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	GAMT: PP3, BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000153308	SCV003844600	benign	not specified	2023-02-13	criteria provided, single submitter	clinical testing	Variant summary: GAMT c.79T>C (p.Tyr27His) results in a 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 0.0028 in 86858 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in GAMT causing Cerebral Creatine Deficiency Syndrome 2 phenotype (0.0011), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.79T>C in individuals affected with Cerebral Creatine Deficiency Syndrome 2 and no experimental evidence demonstrating its impact on protein function have been reported. 11 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely pathogenic n=1, VUS n=2, likely benign n=3, benign n=5). Based on the evidence outlined above, the variant was classified as benign.
GenomeConnect-Association for Creatine Deficiencies, Association for Creatine Deficiencies	RCV001009545	SCV001169640	not provided	Guanidinoacetate methyltransferase (GAMT) deficiency		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 08-22-2014 by GTR ID 26957. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect facilitates ClinVar submission from the Association for Creatine Deficiencies registry and does not attempt to reinterpret the variant.
Elsea Laboratory, Baylor College of Medicine	RCV001127426	SCV001424220	likely pathogenic	Deficiency of guanidinoacetate methyltransferase	2020-04-01	no assertion criteria provided	clinical testing
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001251994	SCV001427740	likely benign	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001127426	SCV001460089	benign	Deficiency of guanidinoacetate methyltransferase	2020-01-11	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000224880	SCV001978379	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000224880	SCV001980165	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003907448	SCV004728895	likely benign	GAMT-related disorder	2020-01-22	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).