Submissions for variant NM_000156.6(GAMT):c.402C>G (p.Tyr134Ter)

dbSNP: rs556829801

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV001780138	SCV004009594	pathogenic	Deficiency of guanidinoacetate methyltransferase	2023-05-25	reviewed by expert panel	curation	The NM_000156.6:c.402C>G (p.Tyr134Ter) variant in GAMT is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 4/6 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 in the South Asian population, which is lower than the ClinGen CCDS VCEP's threshold for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has been detected in one individual with GAMT deficiency (PMID: 19027335). This individual had elevated GAA and low creatine in plasma and significantly decreased creatine peak and visible GAA peak on brain MRS with full GAMT gene sequencing (PMID: 19027335) (PP4_Strong). There is a ClinVar entry for this variant (Variation ID: 947458, 2 star review status) with 3 submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as 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): PVS1, PM2_Supporting, PP4_Strong. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 25, 2023)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001218543	SCV001390429	pathogenic	Cerebral creatine deficiency syndrome	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr134*) 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 (rs556829801, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with guanidinoacetate methyltransferase deficiency (PMID: 19027335). ClinVar contains an entry for this variant (Variation ID: 947458). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001218543	SCV001999921	pathogenic	Cerebral creatine deficiency syndrome	2021-11-02	criteria provided, single submitter	curation	The p.Tyr134Ter variant in GAMT has been reported in 1 individual, in the compound heterozygous state, with cerebral creatine deficiency syndrome (PMID: 19027335) and has been identified in in 0.003% (1/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs556829801). 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#: 947458) and has been interpreted as pathogenic by Invitae. This nonsense variant leads to a premature termination codon at position 134, which is 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 compound heterozygous for this variant is highly specific for cerebral creatine deficiency syndrome based on strict biochemical investigations consistent with disease (PMID: 19027335). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cerebral creatine deficiency syndrome. ACMG/AMP Criteria applied: PVS1, PP4_strong, PM2_supporting (Richards 2015).
Revvity Omics, Revvity	RCV001780138	SCV002024177	pathogenic	Deficiency of guanidinoacetate methyltransferase	2021-06-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001780138	SCV005058881	pathogenic	Deficiency of guanidinoacetate methyltransferase	2023-12-23	criteria provided, single submitter	clinical testing