Submissions for variant NM_000156.6(GAMT):c.403G>T (p.Asp135Tyr)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV003159293	SCV003852716	likely pathogenic	Deficiency of guanidinoacetate methyltransferase	2023-03-23	reviewed by expert panel	curation	The NM_000156.6:c.403G>T (p.Asp135Tyr) variant in GAMT has been identified in one individual with guanidinoacetate methyltransferase deficiency (PMID: 19027335). This variant was identified in 0.001470% (1/68032) of non-Finnish European chromosomes by the Genome Aggregation Database (gnomAD) (PM2_Supporting). The patient previously reported was a reported compound heterozygote that carried a pathogenic variant, c.507_521dup15 (p.C169_S173dup; ClinVar Variation ID: 431959), in unknown phase (PM3_Supporting). This individual showed reduced creatine peak on brain magnetic resonance spectroscopy and elevated plasma GAA with low creatine with full GAMT gene sequencing (PP4_Strong). The p.Asp135Tyr variant is a missense variant that is predicted damaging by in-silico missense predictors (REVEL score 0.938) (PP3). A different missense variant at the same amino acid residue, p.Asp135Asn, has been previously reported pathogenic (ClinVar Variation ID: 573140) (PM5). In summary, this variant meets criteria to be classified as likely pathogenic for guanidinoacetate methyltransferase (GAMT) deficiency. GAMT-specific ACMG/AMP Criteria applied, as specified by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel (CCDS VCEP) (Specifications version 1.1.0): PM2_Supporting, PM3_Supporting, PM5, PP3, PP4_Strong (Richards 2015). (Classification approved by the ClinGen CCDS VCEP on March 23, 2023)
Baylor Genetics	RCV003159293	SCV004198606	likely pathogenic	Deficiency of guanidinoacetate methyltransferase	2023-12-13	criteria provided, single submitter	clinical testing