Submissions for variant NM_000156.6(GAMT):c.623G>A (p.Arg208His)

gnomAD frequency: 0.00003  dbSNP: rs767887772

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV001835926	SCV002600140	uncertain significance	Deficiency of guanidinoacetate methyltransferase	2022-06-06	reviewed by expert panel	curation	The NM_000156.6:c.623G>A variant in GAMT is a missense variant predicted to cause substitution of arginine by histidine at amino acid 208 (p.Arg208His). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00012 (3/24752 alleles) in the African 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 0.279 which is below the threshold of 0.5, evidence that correlates with no impact to GAMT function (BP4). Two additional missense variants at this amino acid position have been reported - c.622C>T (p.Arg208Cys) (ClinVarID: 5442618) and c.623G>C (p.Arg208Pro) (PMID 24415674). The ClinGen CCDS VCEP has classified p.Arg208Pro as likely pathogenic, while p.Arg208Cys has been classified as a VUS (PM5_Supporting). To our knowledge, c.623G>A (p.Arg208His) has not been previously reported in the published literature, but has been noted in ClinVar (ClinVar ID 577478). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0: PM2_Supporting, PM5_Supporting, BP4. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000700249	SCV000828997	uncertain significance	Cerebral creatine deficiency syndrome	2022-10-17	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 208 of the GAMT protein (p.Arg208His). This variant is present in population databases (rs767887772, gnomAD 0.01%). 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: 577478). 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.
Ambry Genetics	RCV002360795	SCV002659452	uncertain significance	Inborn genetic diseases	2017-12-22	criteria provided, single submitter	clinical testing	The p.R208H variant (also known as c.623G>A), located in coding exon 6 of the GAMT gene, results from a G to A substitution at nucleotide position 623. The arginine at codon 208 is replaced by histidine, an amino acid with highly similar properties. 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 alteration remains unclear.
Natera, Inc.	RCV001835926	SCV002087006	uncertain significance	Deficiency of guanidinoacetate methyltransferase	2019-10-28	no assertion criteria provided	clinical testing