Submissions for variant NM_000156.6(GAMT):c.521G>A (p.Trp174Ter)

dbSNP: rs200444143

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV001827125	SCV005903235	pathogenic	Deficiency of guanidinoacetate methyltransferase	2025-03-18	reviewed by expert panel	curation	The NM_000156.6:c.521G>A (p.Trp174Ter) variant in GAMT is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 5 out of a total of 6 exons. The variant occurs at the border of the last 50 nucleotides of the penultimate exon of GAMT. As a result, nonsense-mediated decay may not occur. In that case, >10% of the protein is predicted to be lost (PVS1_Strong). The variant has been identified in a female Spanish patient with clinical features consistent with GAMT deficiency, elevated urine guanidinoacetate, and very low GAMT activity in fibroblasts (PMID: 15108290, 16855203, 21140503) (PP4_Strong). This patient is compound heterozygous for the variant and another variant in GAMT that has been classified as pathogenic by the ClinGen CCDS VCEP, c.59G>C (p.Trp20Ser) (ClinVar Variation ID: 8303; SCV004009593.1). The variants were confirmed to be in trans by parental DNA sequencing. 1 point (PM3). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00002196 (2/91090 alleles; no homozygotes) in the South Asian population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). Another variant resulting in p.Trp174Ter (c.522G>A) (ClinVar Variation ID: 205584) has been reported and has been classified as pathogenic by the ClinGen CCDS VCEP. There is a ClinVar entry for the variant (Variation ID 801414). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency. ACMG/AMP GANT-specific criteria applied, as specified by the ClinGen CCDS VCEP (Version 2.0.0): PVS1_Strong, PM3, PP4_Strong, PM2_Supporting. (Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel on March 18, 2025)
Mendelics	RCV000986197	SCV001135120	pathogenic	not provided	2019-05-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001386710	SCV001587054	pathogenic	Cerebral creatine deficiency syndrome	2024-02-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp174*) in the GAMT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAMT are known to be pathogenic (PMID: 15108290). This variant is present in population databases (rs200444143, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with guanidinoacetate methyltransferase deficiency (PMID: 15108290). ClinVar contains an entry for this variant (Variation ID: 801414). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001386710	SCV001999908	pathogenic	Cerebral creatine deficiency syndrome	2021-11-02	criteria provided, single submitter	curation	The p.Trp174Ter (c.521G>A) variant in GAMT has been reported in 2 individuals with cerebral creatine deficiency syndrome (PMID: 15108290, 19892372) and has been identified in in 0.003% (1/30614) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs200444143). 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 2 affected individuals, 1 was a compound heterozygote that carried a reported likely pathogenic variant in trans, and 1 was a compound heterozygote that carried a reported likely pathogenic variant with unknown phase, which increases the likelihood that the p.Trp174Ter variant is pathogenic (VariationID: 8303; PMID: 15108290, 19892372). This variant has also been reported in ClinVar (Variation ID#: 801414) and has been interpreted as pathogenic by Invitae and Mendelics. In vitro functional studies provide some evidence that the p.Trp174Ter variant may impact protein function (PMID: 21140503). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 174. This alteration 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 compound heterozygous for this variant is highly specific for cerebral creatine deficiency syndrome based on strict biochemical investigations consistent with disease (PMID: 15108290, 19892372). 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, PS3_supporting (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001827125	SCV002511407	pathogenic	Deficiency of guanidinoacetate methyltransferase	2022-04-12	criteria provided, single submitter	clinical testing	Variant summary: GAMT c.521G>A (p.Trp174X) 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 4e-06 in 250896 control chromosomes (gnomAD). c.521G>A has been reported in the literature in individuals affected with Guanidinoactetate Methyltransferase Deficiency (Item_2004, Mercimek-Mahmutoglu_2006, Alcaide_2011). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV001827125	SCV005655104	pathogenic	Deficiency of guanidinoacetate methyltransferase	2024-05-22	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001827125	SCV002087018	pathogenic	Deficiency of guanidinoacetate methyltransferase	2020-12-01	no assertion criteria provided	clinical testing