ClinVar Genomic variation as it relates to human health

The NM_000156.6:c.590T>C variant in GAMT is a missense variant predicted to cause substitution of leucine by proline at amino acid 197 (p.Leu197Pro). This variant has been detected in two unrelated individuals with GAMT deficiency. Of those individuals, one was compound heterozygous for the variant and a likely pathogenic variant, c.526delG, in unknown phase (PMID: 19288536) and one individual was homozygous for the variant (PMID: 16293431) (0.75 points total) (PM3_Supporting). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). One patient with this variant had elevated GAA with low creatine in plasma and elevated GAA with low creatine in urine (PMID: 19288536) and another patient with this variant had elevated GAA with low creatine in plasma, elevated GAA with low creatine in urine, absent creatine peak on brain MRS (PMID: 16293431) (PP4_Strong). Expression of the variant in GAMT-deficient human fibroblast cell line resulted in <5% wild type GAMT activity indicating that this variant may impact protein function (PMID: 24415674) (PS3_Supporting). The computational predictor REVEL gives a score of 0.925 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3). There is no ClinVar entry for this variant. 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): PS3_Supporting, PM2_Supporting, PM3_Supporting, PP4_Strong, PP3. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 25, 2023)

Variant summary: GAMT c.590T>C (p.Leu197Pro) 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 243768 control chromosomes (gnomAD). c.590T>C has been reported in the literature in individuals affected with Guanidinoactetate Methyltransferase Deficiency (Leuzzi_2006, Engelke_2009). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant resulted in no significant enzymatic activity (Mercimek-Mahmutoglu_2014). The following publications have been ascertained in the context of this evaluation (PMID: 16293431, 19288536, 24415674). ClinVar contains an entry for this variant (Variation ID: 2570638). Based on the evidence outlined above, the variant was classified as likely pathogenic.