Submissions for variant NM_000156.6(GAMT):c.662G>A (p.Arg221His)

gnomAD frequency: 0.00009  dbSNP: rs766553422

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000655360	SCV000777290	uncertain significance	Cerebral creatine deficiency syndrome	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 221 of the GAMT protein (p.Arg221His). This variant is present in population databases (rs766553422, 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: 544254). 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 with a negative predictive value of 95%. 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000768230	SCV000898726	uncertain significance	Deficiency of guanidinoacetate methyltransferase	2021-03-30	criteria provided, single submitter	clinical testing	GAMT NM_000156.5 exon 6 p.Arg221His (c.662G>A): This variant has not been reported in the literature and is present in 0.02% (5/23566) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/19-1397407-C-T). This variant is present in ClinVar (Variation ID:544254). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Illumina Laboratory Services, Illumina	RCV000768230	SCV001283285	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.
Ambry Genetics	RCV002360672	SCV002663191	uncertain significance	Inborn genetic diseases	2023-06-02	criteria provided, single submitter	clinical testing	The c.662G>A (p.R221H) alteration is located in exon 6 (coding exon 6) of the GAMT gene. This alteration results from a G to A substitution at nucleotide position 662, causing the arginine (R) at amino acid position 221 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV004808835	SCV005432189	uncertain significance	not provided	2024-11-01	criteria provided, single submitter	clinical testing	GAMT: PM2, PP3
Natera, Inc.	RCV000768230	SCV001460075	uncertain significance	Deficiency of guanidinoacetate methyltransferase	2020-01-17	no assertion criteria provided	clinical testing