Submissions for variant NM_000156.6(GAMT):c.491del (p.Gly164fs)

dbSNP: rs749390953

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV001030778	SCV004009592	pathogenic	Deficiency of guanidinoacetate methyltransferase	2023-05-25	reviewed by expert panel	curation	The NM_000156.6:c.491del (p.Gly164AlafsTer14) variant in GAMT is a frameshift variant predicted to cause a premature stop codon in the last 50 nucleotides of the penultimate exon and therefore to escape nonsense mediated decay. More than 10% of the protein is predicted to be removed. (PVS1_Strong). This variant has been detected in in 7 unrelated individuals with GAMT deficiency, all of whom were homozygous for the variant (PMID: 29302074, PMID: 32214227, PMID: 15234333, PMID: 23660394, PMID: 15108290) (1pt, PM3). One of these individuals had elevated GAA in plasma, elevated GAA in urine, deficient GAMT enzyme activity (<5% wild-type) in fibroblasts, and significantly reduced creatine peak with present GAA peak on brain MRS (PMID: 15234333) and one of these individuals had elevated urine GAA and undetectable GAMT enzyme activity in fibroblasts (PMID: 15108290) (PP4_Strong). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001607 (4/24886 alleles) in the African/African American population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 810628, 2 star review status) with 7 submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for GAMT 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): PVS1_Strong, PM2_Supporting, PM3, PP4_Strong. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 25, 2023)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001030778	SCV001821335	pathogenic	Deficiency of guanidinoacetate methyltransferase	2021-08-21	criteria provided, single submitter	clinical testing	Variant summary: GAMT c.491delG (p.Gly164AlafsX14) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.2e-05 in 250692 control chromosomes. c.491delG has been reported in the literature in multiple individuals affected with Guanidinoactetate Methyltransferase Deficiency (example, Item_2004, Hengel_2020, Mercimek-Mahmutoglu_2006, Comeaux_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001766818	SCV001999913	pathogenic	Cerebral creatine deficiency syndrome	2021-11-02	criteria provided, single submitter	curation	The p.Gly164fs variant in GAMT has been reported in at least 6 individuals with cerebral creatine deficiency syndrome (PMID: 15108290, 32214227, 16855203, 23660394), and has been identified in in 0.02% (4/24886) of African/African-American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs768985121). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of the 6 affected individuals, all of those were homozygotes, which increases the likelihood that the p.Gly164fs variant is pathogenic (PMID: 15108290, 32214227, 16855203, 23660394). This variant has also been reported in ClinVar (Variation ID#: 810628) and has been interpreted as pathogenic by Section for Clinical Neurogenetics (University of Tübingen) and Women's Health and Genetics (Laboratory Corporation of America, LabCorp). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 164 and leads to a premature termination codon 14 amino acids downstream. This termination codon occurs within the terminal 50 bases of the second to last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the GAMT gene is an established disease mechanism in autosomal recessive cerebral creatine deficiency syndrome. The phenotype of individuals homozygous for this variant is highly specific for cerebral creatine deficiency syndrome based on strict biochemical investigations consistent with disease (PMID: 23660394, 15108290). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cerebral creatine deficiency syndrome. ACMG/AMP Criteria applied: PVS1_strong, PM3, PP4_strong, PM2_supporting (Richards 2015).
DASA	RCV001766818	SCV002061233	pathogenic	Cerebral creatine deficiency syndrome	2022-01-05	criteria provided, single submitter	clinical testing	The c.491del;p.(Gly164Alafs*14) is a null frameshift variant (NMD) in the GAMT gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevantexon to the transcript -PVS1_strong. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 810628; PMID: 32214227; 23660394; 16855203) - PS4. The variant is present at low allele frequencies population databases (rs749390953– gnomAD 0.003942%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Gly164Alafs*14) was detected in trans with a pathogenic variant (PMID: 16855203) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001766818	SCV002230002	pathogenic	Cerebral creatine deficiency syndrome	2024-12-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly164Alafs*14) in the GAMT gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 73 amino acid(s) of the GAMT protein. This variant is present in population databases (rs749390953, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with guanidinoacetate methyltransferase (GAMT) deficiency (PMID: 15108290, 23660394). ClinVar contains an entry for this variant (Variation ID: 810628). This variant disrupts a region of the GAMT protein in which other variant(s) (p.Trp174*) have been determined to be pathogenic (PMID: 17171576, 19027335, 23660394, 24268530). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV002255172	SCV002526593	pathogenic	not provided	2022-02-28	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation, as the last 73 amino acids are replaced with 13 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 15234333, 23660394, 19027335, 26003046, 16054853, 15108290, 29302074, 32214227)
Baylor Genetics	RCV001030778	SCV004198571	pathogenic	Deficiency of guanidinoacetate methyltransferase	2023-10-06	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV001030778	SCV004934100	pathogenic	Deficiency of guanidinoacetate methyltransferase	2024-04-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV002255172	SCV005437010	pathogenic	not provided	2024-11-01	criteria provided, single submitter	clinical testing	GAMT: PVS1:Strong, PM2, PM3, PP4:Moderate
Section for Clinical Neurogenetics, University of Tübingen	RCV001030778	SCV001156085	pathogenic	Deficiency of guanidinoacetate methyltransferase	2019-08-01	no assertion criteria provided	research
Natera, Inc.	RCV001030778	SCV002087023	pathogenic	Deficiency of guanidinoacetate methyltransferase	2020-10-07	no assertion criteria provided	clinical testing