Submissions for variant NM_000156.6(GAMT):c.476T>C (p.Leu159Pro)

dbSNP: rs2144636453

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	RCV003159214	SCV003852718	likely pathogenic	Deficiency of guanidinoacetate methyltransferase	2023-03-23	reviewed by expert panel	curation	The NM_000156.6:c.476T>C (p.Leu159Pro) variant in GAMT has been identified in one individual with guanidinoacetate methyltransferase deficiency (PMID: 24415674). This variant is absent in population databases (PM2_Supporting). The patient previously reported was a homozygote for the variant (PMID: 24415674) (PM3_Supporting). This individual showed an absent creatine peak and an absent GAA peak on brain MRS (PP4_Moderate). The p.Leu159Pro variant is a missense variant that is predicted damaging by in-silico missense predictors (REVEL score 0.947) (PP3). This variant was shown to result in undetectable GAMT enzyme activity in GAMT-deficient fibroblasts (PMID: 24415674) (PS3_Supporting). 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): PS3_Supporting, PM2_Supporting, PM3_Supporting, PP3, PP4_Moderate (Richards 2015). (Classification approved by the ClinGen CCDS VCEP on March 23, 2023)
CeGaT Center for Human Genetics Tuebingen	RCV001816225	SCV002063701	pathogenic	not provided	2021-11-01	criteria provided, single submitter	clinical testing