Submissions for variant NM_000156.6(GAMT):c.268G>A (p.Glu90Lys)

dbSNP: rs1569006974

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV003159182	SCV003852724	uncertain significance	Deficiency of guanidinoacetate methyltransferase	2023-02-03	reviewed by expert panel	curation	The NM_000156.6:c.268G>A variant in GAMT is a missense variant that is predicted to result in the substitution of glutamate by lysine at amino acid 90 (p.Glu90Lys). One proband who is homozygous for the variant has been reported. This individual has development delay and seizures, in addition to elevated guanidinoacetate in urine and plasma and low creatine in urine and plasma ( PMID: 24440240). The computational predictor REVEL gives a score of 0.943 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3). To our knowledge, the results of functional studies are not available. The highest population minor allele frequency in gnomAD v2.1.1 is 0.000036 (1/27754 alleles) in the South Asian population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The variant is noted in ClinVar (Variation ID: 916122). In summary, this variant meets the criteria to be classified as a variant of unceratinsignificance for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 1.1.0): PP4_Moderate, PP3, PM3_Supporting, PM2_Supporting.
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV001171628	SCV001334426	pathogenic	not provided	2019-12-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001325103	SCV001516081	uncertain significance	Cerebral creatine deficiency syndrome	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 90 of the GAMT protein (p.Glu90Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with GAMT-related conditions. ClinVar contains an entry for this variant (Variation ID: 916122). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GAMT protein function. 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	RCV001325103	SCV001999927	uncertain significance	Cerebral creatine deficiency syndrome	2021-11-02	criteria provided, single submitter	curation	The p.Glu90Lys variant in GAMT has been reported in 1 individual, in the homozygous state, with cerebral creatine deficiency syndrome (PMID: 24440240) and has been identified in 0.004% (1/27754) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs750232484). 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#: 916122) and has been interpreted as VUS by Invitae and pathogenic by Laboratory of Molecular Genetics (Pr. Bezieau's lab, CHU de Nantes). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. 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: 24440240). In summary, the clinical significance of the p.Glu90Lys variant is uncertain. ACMG/AMP Criteria applied: PM3_supporting, PM2_supporting, PP3, PP4_moderate (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307689	SCV002600568	uncertain significance	not specified	2022-10-19	criteria provided, single submitter	clinical testing	Variant summary: GAMT c.268G>A (p.Glu90Lys) 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 allele was found at a frequency of 4.5e-06 in 224458 control chromosomes (gnomAD). c.268G>A has been reported in the literature as a homozygous occurrence in an individual affected with Cerebral Creatine Deficiency Syndrome 2 (Haas_2014). These data indicate that the variant may be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and as pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Ambry Genetics	RCV002558719	SCV003537661	uncertain significance	Inborn genetic diseases	2021-07-02	criteria provided, single submitter	clinical testing	(Haas, 2014) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.