Submissions for variant NM_000156.6(GAMT):c.22C>A (p.Pro8Thr)

gnomAD frequency: 0.00014  dbSNP: rs776498025

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	RCV001127428	SCV003852704	uncertain significance	Deficiency of guanidinoacetate methyltransferase	2023-02-23	reviewed by expert panel	curation	The NM_000156.6:c.22C>A variant in GAMT is a missense variant that is predicted to result in the substitution of proline by threonine at amino acid 8 (p.Pro8Thr). One patient, who is heterozygous for the variant, has been reported. This individual, who presented with severe global develpomental delay, hypotonia, and intractable seizures, died at 11 months of age. Urine and plasma guanidinoacetate were elevated 2.5 and 1.8 times, respectively. However, on 1H-MRS, creatine peak was about 90% of normal, marginally low, which was not suggestive of GAMT deficiency(PMID: 24415674) (PP4 not applied). GAA-deficient fibroblasts overexpressing the c.22C>A (p.Pro8Thr) variant showed similar GAMT enzyme activity as those transfected with wild-type cDNA (PMID: 24415674) (BS3_Supporting). The computational predictor REVEL gives a score of 0.479 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAMT function (BP4). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00023 (7/30820 alleles) in the European non-Finnish population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 205598). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. GAMT-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Cerebral Creatine Deficiencies VCEP (Specifications Version 1.1.0): BS3_Supporting, BP4, PM2_Supporting. Although this variant meets criteria for a classification of Variant of Uncertain Significance, the ClinGen Cerebral Creatine Deficiencies VCEP considers this variant suspicious for Likely Benign. Future literature may warrant a reclassification of this variant.
GeneDx	RCV000187583	SCV000241177	likely benign	not provided	2020-01-28	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26003046, 24415674)
Ambry Genetics	RCV002317101	SCV000851583	uncertain significance	Inborn genetic diseases	2017-03-07	criteria provided, single submitter	clinical testing	The p.P8T variant (also known as c.22C>A), located in coding exon 1 of the GAMT gene, results from a C to A substitution at nucleotide position 22. The proline at codon 8 is replaced by threonine, an amino acid with highly similar properties. This alteration was found to be heterozygous in one individual with no identifiable second alteration in the GAMT gene who presented with severe global developmental delay, hypotonia, and intractable epilepsy of unknown etiology; however, the individual&rsquo;s MRS imaging was not consistent with guanidinoacetate methyltransferase deficiency (GAMT-D) (Mercimek-Mahmutoglu S et al. Hum. Mutat., 2014 Apr; 35:462-9; Desroches CL et al. Mol. Genet. Genomics, 2015 Dec; 290:2163-71). In addition, functional studies suggested that the alteration did not impact GAMT enzyme activity (Mercimek-Mahmutoglu S et al. Hum. Mutat., 2014 Apr; 35:462-9; Desroches CL et al. Mol. Genet. Genomics, 2015 Dec; 290:2163-71). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000815633	SCV000956094	uncertain significance	Cerebral creatine deficiency syndrome	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 8 of the GAMT protein (p.Pro8Thr). This variant is present in population databases (rs776498025, gnomAD 0.02%). This missense change has been observed in individual(s) with severe GDD, hypotonia, intractable epilepsy (PMID: 24415674). ClinVar contains an entry for this variant (Variation ID: 205598). 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. Experimental studies have shown that this missense change does not substantially affect 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.
Illumina Laboratory Services, Illumina	RCV001127428	SCV001286740	uncertain significance	Deficiency of guanidinoacetate methyltransferase	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Revvity Omics, Revvity	RCV001127428	SCV004235110	uncertain significance	Deficiency of guanidinoacetate methyltransferase	2023-11-02	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001127428	SCV001464193	uncertain significance	Deficiency of guanidinoacetate methyltransferase	2020-01-13	no assertion criteria provided	clinical testing