Submissions for variant NM_000156.6(GAMT):c.491G>A (p.Gly164Asp)

dbSNP: rs760101382

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	RCV002305456	SCV002600146	uncertain significance	Deficiency of guanidinoacetate methyltransferase	2022-06-06	reviewed by expert panel	curation	The NM_000156.6:c.491G>A variant in GAMT is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 164 (p.Gly164Asp). There has been one reported case in literature with this variant; this patient had elevated plasma guanidinoacetate levels on two occasions and is compound heterozygous for the variant and a pathogenic variant in GAMT, c.522G>A (p.Trp174Ter), confirmed in trans by parental testing (PP4, PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 (1/34562 alleles) in the Latino 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 0.919 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3). There is a ClinVar entry for this variant (Variation ID: 203539). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PM3, PP4, PP3, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).
GeneDx	RCV000187566	SCV000241160	likely pathogenic	not provided	2023-11-05	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 23660394)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001300727	SCV001489876	uncertain significance	Cerebral creatine deficiency syndrome	2022-07-25	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 164 of the GAMT protein (p.Gly164Asp). This variant is present in population databases (rs760101382, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of cerebral creatine deficiency syndromes (PMID: 23660394). ClinVar contains an entry for this variant (Variation ID: 205581). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001731508	SCV001983413	uncertain significance	not specified	2021-09-17	criteria provided, single submitter	clinical testing	Variant summary: GAMT c.491G>A (p.Gly164Asp) results in a non-conservative amino acid change located in the Arginine N-methyltransferase 2-like domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250698 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.491G>A has been reported in the literature in one individual affected with Cerebral Creatine Deficiency Syndrome (Comeaux_2013). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001300727	SCV001999915	likely pathogenic	Cerebral creatine deficiency syndrome	2021-11-02	criteria provided, single submitter	curation	The p.Gly164Asp variant in GAMT has been reported in 1 individual, in the compound heterozygous state, with cerebral creatine deficiency syndrome (PMID: 23660394) and has been identified in 0.003% (1/34562) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs760101382). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 205581) and has been interpreted as VUS by Invitae and pathogenic by GeneDx. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of an individual compound heterozygous for this variant is highly specific for cerebral creatine deficiency syndrome based on strict biochemical investigations consistent with disease (PMID: 23660394). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive cerebral creatine deficiency syndrome. ACMG/AMP Criteria applied: PM3, PM2_supporting, PP3, PP4_moderate (Richards 2015).
Ambry Genetics	RCV002345673	SCV002646184	pathogenic	Inborn genetic diseases	2017-07-25	criteria provided, single submitter	clinical testing	The p.G164D pathogenic mutation (also known as c.491G>A), located in coding exon 5 of the GAMT gene, results from a G to A substitution at nucleotide position 491. The glycine at codon 164 is replaced by aspartic acid, an amino acid with similar properties. This mutation was detected in an individual with suspected cerebral creatine deficiency syndrome (CCDS) and elevated plasma guanidinoacetate (GAA) levels who also carried the p.W174* alteration in GAMT on their other allele. In addition, authors show that this mutation is expected to disrupt this intra-turn hydrogen bond due to the unfavorable Phi&ndash;Psi angle created when aspartate is present (Comeaux MS et al. Mol. Genet. Metab., 2013 Jul;109:260-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV002305456	SCV004198576	pathogenic	Deficiency of guanidinoacetate methyltransferase	2023-09-25	criteria provided, single submitter	clinical testing