Submissions for variant NM_000156.6(GAMT):c.578A>G (p.Gln193Arg)

dbSNP: rs2082607477

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV002489844	SCV003852720	uncertain significance	Deficiency of guanidinoacetate methyltransferase	2023-03-23	reviewed by expert panel	curation	The NM_000156.6:c.578A>G (p.Gln193Arg) variant in GAMT has been identified in one individual with guanidinoacetate methyltransferase deficiency (PMID: 23846910). This variant is absent from the Genome Aggregation Database (gnomAD, https://gnomad.broadinstitute.org/) and was identified in 0.021% (2/9,546) chromosomes with no homozygotes in the 4.7KJPN database (PM2_Supporting). This variant has also been reported in ClinVar (Variation ID: 1328978) and was interpreted as a variant of uncertain significance by LabCorp Women's Health and Genetics/Laboratory Corporation of America. The patient previously reported was a reported compound heterozygote that carried a likely pathogenic variant (c.391G>C (p.Gly131Arg; CA402995480; PS3_Supporting, PM2_Supporting, PP3, PP4_Strong). This individual showed absent creatine peak on brain magnetic resonance spectroscopy and elevated urine GAA with low creatine with full GAMT gene sequencing (PP4_Strong). The p.Gln193Arg variant is a missense variant whose impact is uncertain based on in silico missense predictors (REVEL score 0.626). In summary, the clinical significance of the p.Gln193Arg variant is uncertain. 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, PP4_Strong (Richards 2015). (Classification approved by the ClinGen CCDS VCEP on March 23, 2023)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797869	SCV002041496	uncertain significance	not specified	2021-11-16	criteria provided, single submitter	clinical testing	Variant summary: GAMT c.578A>G (p.Gln193Arg) results in a conservative amino acid change located in the Arginine N-methyltransferase 2-like domain (IPR026480) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 242420 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.578A>G has been reported in the literature as a compound heterozygous genotype in at-least one adult individual affected with Cerebral Creatine Deficiency Syndrome 2 and has been subsequently cited by others (example, Akiyama_2014 and Modi_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV002489844	SCV002778897	uncertain significance	Deficiency of guanidinoacetate methyltransferase	2021-11-22	criteria provided, single submitter	clinical testing