Submissions for variant NM_000156.6(GAMT):c.148A>C (p.Met50Leu)

dbSNP: rs104894694

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	RCV000008803	SCV003852709	likely pathogenic	Deficiency of guanidinoacetate methyltransferase	2023-03-09	reviewed by expert panel	curation	The NM_000156.6:c.148A>C (p.Met50Leu) variant in GAMT has been previously reported in one individual with guanidinoacetate methyltransferase deficiency (PMID: 17101918). This variant is absent from population databases (PM2_Supporting). The affected individual previously reported (PMID: 17101918) was a homozygote for the variant and had a low creatine peak on brain MRS, elevated urinary GAA, low creatine/creatinine ratio, with DNA sequence analysis of GAMT (PM3_Supporting, PP4_Strong). The p.Met50Leu variant is a missense variant that is predicted damaging by in-silico missense predictors (REVEL score 0.923) (PP3). This variant was shown to result in undetectable GAMT enzymatic activity when transfected into 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_Strong (Classification approved by the ClinGen CCDS VCEP on March 9, 2023)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851745	SCV002140605	uncertain significance	Cerebral creatine deficiency syndrome	2021-08-29	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with leucine at codon 50 of the GAMT protein (p.Met50Leu). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and leucine. This missense change has been observed in individual(s) with GAMT deficiency (PMID: 24415674). ClinVar contains an entry for this variant (Variation ID: 8305). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects GAMT function (PMID: 24415674). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000008803	SCV004809908	likely pathogenic	Deficiency of guanidinoacetate methyltransferase	2024-04-04	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000008803	SCV005420571	likely pathogenic	Deficiency of guanidinoacetate methyltransferase	2024-10-04	criteria provided, single submitter	research	PS3,PM3(strong),PM2,PP3,PP4
OMIM	RCV000008803	SCV000029013	pathogenic	Deficiency of guanidinoacetate methyltransferase	2006-11-14	no assertion criteria provided	literature only