ClinVar Genomic variation as it relates to human health

The NM_000156.6:c.522G>A (p.Trp174Ter) variant is a nonsense variant in the last 50bp of the penultimate exon of GAMT, predicted to cause a premature stop codon in the last 50 nucleotides of the penultimate exon of the gene and therefore to escape nonsense mediated decay. More than 10% of the protein is predicted to be removed (PVS1_Strong). At least six probands and two siblings have been reported with clinical and biochemical features consistent with GAMT deficiency including 3 probands and one sibling with elevated plasma GAA (PMID 23660394, https://adc.bmj.com/content/103/2/e1.24), 1 proband with enzyme deficiency (PMID 17171576), 2 probands with reduced plasma creatine, elevated plasma GAA, and reduced creatine peak on MRS (PMID 23583224, 24071436), and a sibling of one of these patients with reduced plasma creatine and elevated plasma GAA (PMID 23583224) (PP4_Strong). Of these probands 4 are compound heterozygous for the variant and a variant that is classified as pathogenic by the ClinGen CCDS VCEP, c.327G>A, phase unknown (PMIDs 17171576, 19027335, 23583224, 23660394, 24071436, 24268530, https://adc.bmj.com/content/103/2/e1.24 (PM3). Another two probands are compound heterozygous for the variant and a missense variant, either c.491G>A (p.Gly164Asp) or c.505T>C (p.Cys169Arg) (PMID 23660394, 24268530). The in trans data from these patients will be used in the assessment of the missense variants and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 (7/113306 alleles) in the European non-Finnish population, which is less that 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: 205584). 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 CCDS VCEP (Specifications Version 1.1.0): PVS1_Strong, PP4_Strong, PM3, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).

The GAMT c.522G>A (p.Trp174Ter) variant has been reported in at least six studies and is found in at least eight individuals with guanidinoacetate methyltransferase (GAMT) deficiency in a compound heterozygous state, including one affected sibling pair (Verhoeven et al. 2005; Morris et al. 2007; Dhar et al. 2009; Viau et al. 2013; El-Gharbawy et al. 2013; Comeaux et al. 2013). Across the studies, individuals displayed a biochemical profile consistent with GAMT deficiency including decreased creatine and elevated guanidinoacetate (GAA) levels in urine or serum as compared to controls or laboratory reference values. Additionally, Morris et al. (2007) demonstrated no detectable GAMT activity in individual fibroblasts. Control data are unavailable for this variant, which is reported at a frequency of 0.00006 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence and due to the potential impact of stop-gained variants, the p.Trp174Ter variant is classified as pathogenic for guanidinoacetate methyltransferase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 63 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 17171576, 19027335, 15108290, 24071436, 23583224, 24268530, 23660394, 16169544, 26003046, 34389248)

This sequence change creates a premature translational stop signal (p.Trp174*) in the GAMT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAMT are known to be pathogenic (PMID: 15108290). This variant is present in population databases (rs370421531, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with guanidinoacetate methyltransferase deficiency (PMID: 17171576, 19027335, 23583224, 23660394, 24071436, 24268530). ClinVar contains an entry for this variant (Variation ID: 205584). For these reasons, this variant has been classified as Pathogenic.

Variant summary: GAMT c.522G>A (p.Trp174X) 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. The variant allele was found at a frequency of 2.8e-05 in 246008 control chromosomes (gnomAD). c.522G>A has been reported in the literature in multiple individuals affected with creatine deficiency syndromes and Guanidinoactetate methyltransferase deficiency. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The p.Trp174Ter (c.522G>A) variant in GAMT has been reported in at least 6 individuals with cerebral creatine deficiency syndrome (PMID: 19027335, 23660394, 24071436, 24268530) and has been identified in in 0.006% (7/113306) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs370421531). 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. Of the at least 6 affected individuals, 3 were compound heterozygotes that carried a reported pathogenic variant with unknown phase, which increases the likelihood that the p.Trp174Ter variant is pathogenic (Variation ID: 21065, 205581; PMID: 19027335, 23660394, 24071436, 24268530). This variant has also been reported in ClinVar (Variation ID#: 205584) and has been interpreted as pathogenic by Fulgent Genetics, GeneDx, Illumina Clinical Services Laboratory (Illumina), Women's Health and Genetics (Laboratory Corporation of America, LabCorp), Invitae, and Natera, Inc. This nonsense variant leads to a premature termination codon at position 174. This alteration occurs within the terminal 50 bases of the second to last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the GAMT gene is an established disease mechanism in autosomal recessive cerebral creatine deficiency syndrome. The phenotype of individuals homozygous or compound heterozygous for this variant is highly specific for cerebral creatine deficiency syndrome based on strict biochemical investigations consistent with disease (PMID: 23660394, 24071436, 19027335). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cerebral creatine deficiency syndrome. ACMG/AMP Criteria applied: PVS1_strong, PM3, PM2_supporting, PP4_strong (Richards 2015).

The GAMT c.522G>A variant is predicted to result in premature protein termination (p.Trp174*). This variant was reported in the compound heterozygous in multiple individuals with guanidinoacetate methyltransferase deficiency (see, for example, Morris et al. 2007. PubMed ID: 17171576; Dhar et al. 2008. PubMed ID: 19027335). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-1398963-C-T). Nonsense variants in GAMT are expected to be pathogenic. This variant is interpreted as pathogenic.

Variant interpreted as Pathogenic and reported on 12-08-2009 by GTR ID 1006. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect facilitates ClinVar submission from the Association for Creatine Deficiencies registry and does not attempt to reinterpret the variant.