Submissions for variant NM_000156.6(GAMT):c.707G>C (p.Gly236Ala)

gnomAD frequency: 0.00011  dbSNP: rs201029006

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	RCV001123244	SCV002600160	uncertain significance	Deficiency of guanidinoacetate methyltransferase	2022-06-06	reviewed by expert panel	curation	The NM_000156.6:c.707G>C (p.Gly236Ala) variant in GAMT is a missense variant predicted to cause substitution of glycine by alanine at amino acid 236 (p.Gly236Ala). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00015 (19/126040 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). The computational predictor REVEL gives a score of 0.323 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAMT function (BP4). To our knowledge, this variant has not been reported in the published literature. This variant is noted in ClinVar (ID 205596). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 1.1.00): PM2_Supporting, BP4. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).
GeneDx	RCV000711736	SCV000241175	likely benign	not provided	2021-05-24	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV000464619	SCV000552951	uncertain significance	Cerebral creatine deficiency syndrome	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 236 of the GAMT protein (p.Gly236Ala). This variant is present in population databases (rs201029006, gnomAD 0.02%). 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: 205596). 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) performed at Invitae indicates that this missense variant is not expected to disrupt 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.
Athena Diagnostics	RCV000711736	SCV000842125	uncertain significance	not provided	2017-09-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002317100	SCV000850288	uncertain significance	Inborn genetic diseases	2016-10-28	criteria provided, single submitter	clinical testing	The p.G236A variant (also known as c.707G>C), located in coding exon 6 of the GAMT gene, results from a G to C substitution at nucleotide position 707. The glycine at codon 236 is replaced by alanine, an amino acid with similar properties. This variant was previously reported in the SNPDatabase as rs201029006. Based on data from the 1000 Genomes Project, the C allele has an overall frequency of approximately 0.05% (1/2098) total alleles studied. The highest observed frequency was 0.59% (1/170) British alleles. Based on data from the NHLBI Exome Sequencing Project (ESP), the C allele has an overall frequency of approximately 0.02% (2/12994) total alleles studied and 0.02% (2/8594) European American alleles. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Illumina Laboratory Services, Illumina	RCV001123244	SCV001282063	uncertain significance	Deficiency of guanidinoacetate methyltransferase	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Natera, Inc.	RCV001123244	SCV001460074	uncertain significance	Deficiency of guanidinoacetate methyltransferase	2020-01-17	no assertion criteria provided	clinical testing