ClinVar Miner

Submissions for variant NM_000156.6(GAMT):c.520T>C (p.Trp174Arg)

dbSNP: rs891042971
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen RCV003482165 SCV004227932 likely pathogenic Deficiency of guanidinoacetate methyltransferase 2023-10-12 reviewed by expert panel curation The NM_000156.6:c.520T>C variant in GAMT is a missense variant predicted to cause substitution of tryptophan by arginine at amino acid 174 (p.Trp174Arg). This variant has been detected in two individuals with GAMT deficiency. Of those individuals, both were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and both of those were confirmed in trans by parental testing (PMID 35588794) (PM3_Strong). At least one patient with this variant had elevated GAA and low creatine in plasma (PP4). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001 (1/113,296 alleles) in the non-Finnish European population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.808 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3). There is a ClinVar entry for this variant (Variation ID: 1420866). In summary, this variant meets the criteria to be classified as likely 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 1.1.0): PM3_Strong, PP3, PP4, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on Oct. 12, 2023)
Labcorp Genetics (formerly Invitae), Labcorp RCV001943659 SCV002188587 uncertain significance Cerebral creatine deficiency syndrome 2021-08-27 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 174 of the GAMT protein (p.Trp174Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with GAMT-related conditions. 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"). 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.
Fulgent Genetics, Fulgent Genetics RCV003482165 SCV005655105 likely pathogenic Deficiency of guanidinoacetate methyltransferase 2024-02-25 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.