Submissions for variant NM_000156.6(GAMT):c.526dup (p.Glu176fs)

dbSNP: rs2144636246

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	RCV003159218	SCV003852719	pathogenic	Deficiency of guanidinoacetate methyltransferase	2023-03-23	reviewed by expert panel	curation	The NM_000156.6:c.526dup (p.Glu176GlyfsTer15) variant in GAMT has been previously reported in at least one individual with guanidinoacetate methyltransferase deficiency (PMID: 15108290). This variant is absent in population databases (PM2_Supporting). This variant has been reported in ClinVar (Variation ID: 1409758) and has been interpreted as pathogenic by Invitae. The individual who was previously reported was a compound heterozygote; however, this occurrence was counted for evidence for PM3 for the other variant and thus not used here to prevent circularity in the use of PM3 (PMID: 15108290). This individual showed elevated urinary GAA and partially absent creatine peak and absent GAA peak on brain MRS with full GAMT gene sequencing (PMID: 15108290) (PP4_Strong). The p.Glu176GlyfsTer15 variant is a frameshift variant at amino acid position 176 that is predicted to lead to premature termination 15 amino acids downstream. As the variant results in termination downstream of the last 50 base pairs of the penultimate exon of the GAMT gene, nonsense-mediated decay is not predicted; however, the variant results in removal of >10% of the encoded protein (PVS1_Strong). In summary, this variant meets criteria to be classified as 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): PVS1_Strong, PM2_Supporting, PP4_Strong (Richards 2015). (Classification approved by the ClinGen CCDS VCEP on March 23, 2023)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001913912	SCV002179311	pathogenic	Cerebral creatine deficiency syndrome	2021-10-05	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the GAMT protein in which other variant(s) (p.Q193*) have been determined to be pathogenic (PMID: 23234264, 31130284). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This premature translational stop signal has been observed in individual(s) with guanidinoacetate methyltransferase deficiency (PMID: 15108290, 24415674). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu176Glyfs*15) in the GAMT gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 61 amino acid(s) of the GAMT protein.
Baylor Genetics	RCV003159218	SCV004198593	pathogenic	Deficiency of guanidinoacetate methyltransferase	2023-04-25	criteria provided, single submitter	clinical testing