Submissions for variant NM_000156.6(GAMT):c.59G>T (p.Trp20Leu)

dbSNP: rs80338734

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV003334006	SCV004042610	uncertain significance	Deficiency of guanidinoacetate methyltransferase	2023-09-13	reviewed by expert panel	curation	The NM_000156.6:c.59G>T variant in GAMT is a missense variant that is predicted to result in the substitution of tryptophan by leucine at amino acid 20 (p.Trp20Leu). To our knowledge, this variant has not been reported in individuals with GAMT deficiency and the result of functional studies are not available. The computational predictor REVEL gives a score of 0.804 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3). Another missense variant, c.59G>C (p.Trp20Ser) (ClinVar Variation ID: 8303)) has been reported at the same amino acid position and has been classified as pathogenic for GAMT deficiency by the ClinGen CCDS VCEP (PM5). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 588631, 1 star review status). In summary, this variant meets the criteria to be classified as uncertain significance 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 1.1.0): PM2_Supporting, PM5, PP3. (Classification approved by the ClinGen CCDS VCEP, Sept 12, 2023)
Ambry Genetics	RCV002313571	SCV000848669	likely pathogenic	Inborn genetic diseases	2017-01-05	criteria provided, single submitter	clinical testing	The p.W20L variant (also known as c.59G>T), located in coding exon 1 of the GAMT gene, results from a G to T substitution at nucleotide position 59. The tryptophan at codon 20 is replaced by leucine, an amino acid with similar properties. One disease-causing mutation, p.W20S, has been described in the same codon. Based on internal structural assessment, this alteration will weaken binding of the substrate S-adenosyl-methinine, impairing protein function {Unpublished structure - PDB: 3ORH}. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001051211	SCV001215354	uncertain significance	Cerebral creatine deficiency syndrome	2022-08-22	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with leucine, which is neutral and non-polar, at codon 20 of the GAMT protein (p.Trp20Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GAMT-related conditions. ClinVar contains an entry for this variant (Variation ID: 588631). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Trp20 amino acid residue in GAMT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15651030, 16855203, 17336114). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307606	SCV002600733	uncertain significance	not specified	2022-10-27	criteria provided, single submitter	clinical testing	Variant summary: GAMT c.59G>T (p.Trp20Leu) results in a non-conservative amino acid change located in the Arginine N-methyltransferase 2-like domain (IPR026480) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 74462 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.59G>T in individuals affected with Cerebral Creatine Deficiency Syndrome 2 and no experimental evidence demonstrating its impact on protein function have been reported. Another variant in the same (highly conserved) nucleotide and amino acid residue (c.59G>C, p.Trp20Ser) is classified as pathogenic by our laboratory, providing moderate evidence of pathogenicity for c.59G>T. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.