Submissions for variant NM_000156.6(GAMT):c.224C>T (p.Ala75Val)

gnomAD frequency: 0.00001  dbSNP: rs1441030187

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV001835900	SCV003852706	pathogenic	Deficiency of guanidinoacetate methyltransferase	2023-03-09	reviewed by expert panel	curation	The NM_000156.6:c.224C>T variant in GAMT is a missense variant that is predicted to result in the substitution of alanine by valine at amino acid 75 (p.Ala75Val). One patient, with mild intellectual disability, anti-epileptic drug-responsive seizures, and stereotypic movements has been reported with creatine and guanidinoacetate peak absent on MRS, bilateral thalami increased on MRI, and urine guanidinoacetate levels between 1.1 and 12 times above the upper limit of reference range (PP4_Strong). This individual is homozygous for the variant (PM3_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00007 (1/15028 alleles) in the African population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). GAMT-deficient fibroblasts transfected with the variant showed <15% wild-type enzyme activity (PMID: 24415674). The computational predictor REVEL gives a score of 0.86 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3). There is a ClinVar entry for this variant (Variation ID: 544251). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PP4_Strong, PP3, PS3_Supporting, PM2_Supporting, PM3_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000655356	SCV000777286	uncertain significance	Cerebral creatine deficiency syndrome	2022-06-02	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 75 of the GAMT protein (p.Ala75Val). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with a positive newborn screening result for GAMT-related disease (PMID: 24415674). ClinVar contains an entry for this variant (Variation ID: 544251). 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: "Probably Damaging"; Align-GVGD: "Class C15"). 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000655356	SCV001999929	likely pathogenic	Cerebral creatine deficiency syndrome	2021-11-02	criteria provided, single submitter	curation	The p.Ala75Val variant in GAMT has been reported in 1 homozygous individual with cerebral creatine deficiency syndrome (PMID: 24415674) and has been identified in 0.007% (1/15028) of African/African-American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1441030187). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 544251) and has been interpreted as VUS by Invitae. In vitro functional studies provide some evidence that the p.Ala75Val variant may slightly impact protein function (PMID: 24415674). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. The phenotype of individuals homozygous or compound heterozygous for this variant is highly specific for cerebral creatine deficiency syndrome based on strict biochemical investigations consistent with disease (PMID: 24415674). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive cerebral creatine deficiency syndrome. ACMG/AMP Criteria applied: PM3_supporting, PM2_supporting, PS3_supporting, PP3, PP4_strong (Richards 2015).
Baylor Genetics	RCV001835900	SCV004198588	likely pathogenic	Deficiency of guanidinoacetate methyltransferase	2024-03-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001835900	SCV005395148	likely pathogenic	Deficiency of guanidinoacetate methyltransferase	2024-09-09	criteria provided, single submitter	clinical testing	Variant summary: GAMT c.224C>T (p.Ala75Val) results in a non-conservative amino acid change located in the Arginine N-methyltransferase 2-like domain (IPR026480) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.1e-05 in 239744 control chromosomes. c.224C>T has been reported in the literature in a homozygous individual affected with Guanidinoactetate Methyltransferase Deficiency (Mercimek-Mahmutoglu_2014) and was identified in as an unspecified genotype in an individual undergoing multigene panel testing for epilepsy and neurodevelopmental disorders, although no further clinical information was provided (Lindy_2018) . These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The variant exhibited <4% activity versus the WT protein when transfected into a GAMT-deficient human fibroblast cell line (Mercimek-Mahmutoglu_2014). The following publications have been ascertained in the context of this evaluation (PMID: 29655203, 24415674). ClinVar contains an entry for this variant (Variation ID: 544251). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV001835900	SCV005655119	likely pathogenic	Deficiency of guanidinoacetate methyltransferase	2024-04-07	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001835900	SCV002087050	uncertain significance	Deficiency of guanidinoacetate methyltransferase	2020-09-18	no assertion criteria provided	clinical testing