Submissions for variant NM_000156.6(GAMT):c.25A>G (p.Ile9Val)

gnomAD frequency: 0.00001  dbSNP: rs1555777381

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519092	SCV000617902	uncertain significance	not provided	2017-12-27	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the GAMT gene. The I9V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The I9V variant is not observed in large population cohorts (Lek et al., 2016). The I9V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Ambry Genetics	RCV002314907	SCV000848589	uncertain significance	Inborn genetic diseases	2016-12-23	criteria provided, single submitter	clinical testing	The p.I9V variant (also known as c.25A>G), located in coding exon 1 of the GAMT gene, results from an A to G substitution at nucleotide position 25. The isoleucine at codon 9 is replaced by valine, an amino acid with highly similar properties. This amino acid position is highly 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 alteration remains unclear.
Illumina Laboratory Services, Illumina	RCV001127427	SCV001286739	uncertain significance	Deficiency of guanidinoacetate methyltransferase	2018-01-13	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001209203	SCV001380626	uncertain significance	Cerebral creatine deficiency syndrome	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 9 of the GAMT protein (p.Ile9Val). This variant is not present in population databases (gnomAD no frequency). 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: 449597). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Baylor Genetics	RCV001127427	SCV001520374	uncertain significance	Deficiency of guanidinoacetate methyltransferase	2019-10-24	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
PreventionGenetics, part of Exact Sciences	RCV003419906	SCV004108628	uncertain significance	GAMT-related disorder	2022-12-07	criteria provided, single submitter	clinical testing	The GAMT c.25A>G variant is predicted to result in the amino acid substitution p.Ile9Val. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Breakthrough Genomics, Breakthrough Genomics	RCV000519092	SCV005192451	uncertain significance	not provided		criteria provided, single submitter	not provided
Natera, Inc.	RCV001127427	SCV002087065	uncertain significance	Deficiency of guanidinoacetate methyltransferase	2020-07-17	no assertion criteria provided	clinical testing