Submissions for variant NM_000156.6(GAMT):c.227C>T (p.Ser76Leu)

gnomAD frequency: 0.00036  dbSNP: rs150338273

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000420649	SCV000227036	uncertain significance	not provided	2017-04-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000420649	SCV000241153	uncertain significance	not provided	2025-01-31	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that S76L does not damage the protein function (PMID: 26319512); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26003046, 28758966, 26319512)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000420649	SCV000511365	uncertain significance	not provided	2017-01-09	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000470154	SCV000552949	uncertain significance	Cerebral creatine deficiency syndrome	2022-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 76 of the GAMT protein (p.Ser76Leu). This variant is present in population databases (rs150338273, gnomAD 0.05%). 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: 195022). 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: 26319512). 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.
Ambry Genetics	RCV002317012	SCV000849600	uncertain significance	Inborn genetic diseases	2023-12-18	criteria provided, single submitter	clinical testing	The c.227C>T (p.S76L) alteration is located in exon 2 (coding exon 2) of the GAMT gene. This alteration results from a C to T substitution at nucleotide position 227, causing the serine (S) at amino acid position 76 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV000764185	SCV000895187	uncertain significance	Deficiency of guanidinoacetate methyltransferase	2018-10-31	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000764185	SCV000898728	uncertain significance	Deficiency of guanidinoacetate methyltransferase	2021-03-30	criteria provided, single submitter	clinical testing	GAMT NM_000156.5 exon 2 p.Ser76Leu (c.227C>T): This variant has been reported in the literature in 1 individual, but without phenotype information (Mercimek-Mahmutoglu 2016 PMID:26319512). This variant is present in 0.05% (66/123594) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/19-1399892-G-A). This variant is present in ClinVar (Variation ID:195022). Evolutionary conservation suggests that this variant may not impact the protein; computational predictive tools for this variant are unclear. Functional studies suggest a benign effect of this variant. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Illumina Laboratory Services, Illumina	RCV000764185	SCV001286736	uncertain significance	Deficiency of guanidinoacetate methyltransferase	2017-04-27	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.
Breakthrough Genomics, Breakthrough Genomics	RCV000420649	SCV005192450	uncertain significance	not provided		criteria provided, single submitter	not provided
Natera, Inc.	RCV000764185	SCV001460086	uncertain significance	Deficiency of guanidinoacetate methyltransferase	2020-01-17	no assertion criteria provided	clinical testing