ClinVar

Description

The NM_000156.6(GAMT):c.11_36dup (p.Gly13ProfsTer38) variant in GAMT (also reported as c.36_c.37ins26) is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 1/6 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD v2.1.1. However, the read depth is <20X at this position and therefore allele frequency data cannot be accurately assessed. Three individuals with biochemical and clinical features consistent with GAMT deficiency have been described including two with reduced creatine peak and guanidinoacetate (GAc) peak on MRS as well as elevated GAc in serum (PMID 19027335, 23660394, 24415674, 29506905) and one with deficient GAMT activity in fibroblasts (PMID 24415674) (PP4_Strong). These individuals are all compound heterozygous for the variant and a second variant in GAMT, phase unknown, including c.327G>A (PMID 19027335, 23660394; pathogenic based on assessment with the ClinGen CCDS VCEP; 0.5 points), c.133T>A (p.Trp45Arg), and c.439C>T (p.His147Tyr). The in trans data for the patients with c.133T>A (p.Trp45Arg) and c.439C>T (p.His147Tyr) will be used in the assessment of those variants and is not included here in order to avoid circular logic (PM3_Supporting). There is a ClinVar entry for this variant (Variation ID: 858462). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency. GAMT-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Cerebral Creatine Deficiencies VCEP (Specifications Version 1.1.0): PVS1, PP4_Strong, PM3_Supporting. (Classification approved by the ClinGen CCDS VCEP, September 12, 2023)