ClinVar Genomic variation as it relates to human health

The NM_000156.6:c.145del (p.Tyr49Ilefs*65) variant in GAMT is a frameshift variant that is predicted to cause a premature stop codon in biologically-relevant-exon 3/6, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). A Spanish patient, who is homozygous for the variant, has been reported with clinical symptoms consistent with GAMT deficiency, elevated guanidinoacetate in urine and plasma, and deficient GAMT activity in fibroblasts (PMID: 19892372, 21140503) (PP4_Strong, PM3_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0000373 (1/26808 alleles) in the Lation/Admixed American population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 695019). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (CCDS VCEP) (Specifications Version 1.1.0): PVS1, PP4_Strong, PM2_Supporting, PM3_Supporting. (Classification approved by the ClinGen CCDS VCEP on Sept. 14, 2023)

This variant was identified in composite heterozygosity with another variant in the same gene in a female patient with IDD. The unaffected parents are both carriers of one of the two variants in the same gene, while the affected brother also harbours both variants in composite heterozygosity

Variant summary: GAMT c.145delT (p.Tyr49IlefsX65) 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 6.2e-06 in 162428 control chromosomes. c.145delT has been reported in the literature in at least one individual affected with Guanidinoactetate methyltransferase deficiency (Alcaide_2011). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Alcaide_2011). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The c.145del variant in GAMT has been reported in 1 individual, in the homozygous state, with cerebral creatine deficiency syndrome (PMID: 19892372) and has been identified in 0.004% (1/26808) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1384688313). 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. This variant has also been reported in ClinVar (Variation ID#: 695019) and has been interpreted as pathogenic by Integrated Genetics (Laboratory Corporation of America) and Center of Genomic medicine (Geneva, University Hospital of Geneva). In vitro functional studies provide evidence that the c.145del variant impacts protein function (PMID: 21140503). However, these types of assays may not accurately represent biological function. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 49 and leads to a premature termination codon 16 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the GAMT gene is an established disease mechanism in autosomal recessive cerebral creatine deficiency syndrome. The phenotype of an individual homozygous for this variant is highly specific for cerebral creatine deficiency syndrome based on strict biochemical investigations consistent with disease (PMID: 21140503). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cerebral creatine deficiency syndrome. ACMG/AMP Criteria applied: PM3_supporting, PVS1, PS3, PP4, PM2_supporting (Richards 2015).