rs886054247
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP3PM2_SupportingPP4_StrongPM3_StrongPS3_Supporting
This summary comes from the ClinGen Evidence Repository: The NM_000156.6:c.133T>A variant in GAMT is a missense variant predicted to cause substitution of tryptophan by arginine at amino acid 45 (p.Trp45Arg). This variant has been detected in 4 unrelated individuals with GAMT deficiency (PMID:24415674, PMID:29506905, PMID:23660394, PMID:24268530). Of those individuals, one was homozygous for the variant (PMID:29506905), two were compound heterozygous for the variant and a pathogenic variant, c.327G>A, in trans (phase confirmed by parental testing) (PMID:24415674, PMID:23660394), and two were compound heterozygous for the variant and a pathogenic variant, c.327G>A, with phase unknown (PMID:24268530) (3pts total, PM3_Strong). One of these individuals had an absent creatine peak and present GAA peak on brain MRS and elevated GAA in urine (PMID:24415674) (PP4_Strong). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 in the European (non-Finnish) population, which is lower than the ClinGen CCDS VCEP's threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). Expression of the variant in GAMT-deficient fibroblasts resulted in undetectable GAMT activity indicating that this variant may impact protein function (PMID:24415674)(PS3_Supporting). The computational predictor REVEL gives a score of 0.95 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: 328352). In summary, this variant meets the criteria to be classified as pathogenic 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): PS3_Supporting, PM2_Supporting, PM3_Strong, PP3, PP4_Strong.(Classification approved by the ClinGen CCDS VCEP on Sept. 14, 2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10651554/MONDO:0012999/026
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000076 ( 0 hom. )
Consequence
GAMT
NM_000156.6 missense
NM_000156.6 missense
Scores
16
1
2
Clinical Significance
Conservation
PhyloP100: 8.92
Genes affected
GAMT (HGNC:4136): (guanidinoacetate N-methyltransferase) The protein encoded by this gene is a methyltransferase that converts guanidoacetate to creatine, using S-adenosylmethionine as the methyl donor. Defects in this gene have been implicated in neurologic syndromes and muscular hypotonia, probably due to creatine deficiency and accumulation of guanidinoacetate in the brain of affected individuals. Two transcript variants encoding different isoforms have been described for this gene. Pseudogenes of this gene are found on chromosomes 2 and 13. [provided by RefSeq, Feb 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PS3
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PM3
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.
PP4
For more information check the summary or visit ClinGen Evidence Repository.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| GAMT | NM_000156.6 | c.133T>A | p.Trp45Arg | missense_variant | 1/6 | ENST00000252288.8 | NP_000147.1 | |
| GAMT | NM_138924.3 | c.133T>A | p.Trp45Arg | missense_variant | 1/5 | NP_620279.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| GAMT | ENST00000252288.8 | c.133T>A | p.Trp45Arg | missense_variant | 1/6 | 1 | NM_000156.6 | ENSP00000252288 | P1 | |
| GAMT | ENST00000447102.8 | c.133T>A | p.Trp45Arg | missense_variant | 1/5 | 2 | ENSP00000403536 | |||
| GAMT | ENST00000640762.1 | c.112+21T>A | intron_variant | 5 | ENSP00000492031 |
Frequencies
GnomAD3 genomes 0.0000461 AC: 7AN: 152002Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000249 AC: 4AN: 160944Hom.: 0 AF XY: 0.0000110 AC XY: 1AN XY: 91176
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GnomAD4 exome AF: 0.0000765 AC: 106AN: 1386396Hom.: 0 Cov.: 31 AF XY: 0.0000668 AC XY: 46AN XY: 688466
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GnomAD4 genome 0.0000461 AC: 7AN: 152002Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74262
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Deficiency of guanidinoacetate methyltransferase Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 02, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 28, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | The GAMT c.133T>A (p.Trp45Arg) variant has been reported in three studies in which it is found in a compound heterozygous state in five individuals with guanidinoacetate methyltransferase deficiency, including two siblings. In four individuals, the variant was detected in trans with a known pathogenic splicing defect, and in one subject the variant was detected in trans with a frameshift variant (Comeaux et al. 2013; Stockler-Ipsirogulu et al. 2014; Mercimek-Mahmutoglu et al. 2014). Control data are unavailable for the p.Trp45Arg variant, which is also not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. The Trp45 residue is highly conserved. Functional studies by Mercimek-Mahmutoglu et al. (2014) have demonstrated that the p.Trp45Arg variant results in decreased protein expression and undetectable enzyme activity. Protein structure modelling predicts that the p.Trp45Arg variant would cause a stereochemical clash and likely alter protein folding (Comeaux et al. 2013). Based on the collective evidence, the p.Trp45Arg variant is classified as pathogenic for guanidinoacetate methyltransferase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
| Pathogenic, reviewed by expert panel | curation | ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen | Nov 08, 2023 | The NM_000156.6:c.133T>A variant in GAMT is a missense variant predicted to cause substitution of tryptophan by arginine at amino acid 45 (p.Trp45Arg). This variant has been detected in 4 unrelated individuals with GAMT deficiency (PMID: 24415674, PMID: 29506905, PMID: 23660394, PMID: 24268530). Of those individuals, one was homozygous for the variant (PMID: 29506905), two were compound heterozygous for the variant and a pathogenic variant, c.327G>A, in trans (phase confirmed by parental testing) (PMID: 24415674, PMID: 23660394), and two were compound heterozygous for the variant and a pathogenic variant, c.327G>A, with phase unknown (PMID: 24268530) (3pts total, PM3_Strong). One of these individuals had an absent creatine peak and present GAA peak on brain MRS and elevated GAA in urine (PMID: 24415674) (PP4_Strong). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 in the European (non-Finnish) population, which is lower than the ClinGen CCDS VCEP's threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). Expression of the variant in GAMT-deficient fibroblasts resulted in undetectable GAMT activity indicating that this variant may impact protein function (PMID: 24415674)(PS3_Supporting). The computational predictor REVEL gives a score of 0.95 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: 328352). In summary, this variant meets the criteria to be classified as pathogenic 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): PS3_Supporting, PM2_Supporting, PM3_Strong, PP3, PP4_Strong. (Classification approved by the ClinGen CCDS VCEP on Sept. 14, 2023) - |
Cerebral creatine deficiency syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Nov 02, 2021 | The p.Trp45Arg variant in GAMT has been reported in 5 individuals with cerebral creatine deficiency syndrome (PMID: 23660394, 24268530, 24415674, 29506905), segregated with disease in 1 affected relative from 1 family (PMID: 24415674), and has been identified in 0.005% (4/73650) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs886054247). 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. Of the 5 affected individuals, 1 of those was a homozygote, 2 were compound heterozygotes that carried reported pathogenic variants in trans, and 2 were compound heterozygotes that carried a reported pathogenic variant with unknown phase, which increases the likelihood that the p.Trp45Arg variant is pathogenic (VariationID: 21065, 858462; PMID: 23660394, 24268530, 24415674, 29506905). This variant has also been reported in ClinVar (Variation ID#: 328352) and has been interpreted as pathogenic by Illumina Clinical Services Laboratory (Illumina) and Invitae. In vitro functional studies provide some evidence that the p.Trp45Arg variant may slightly impact protein function (PMID: 24415674). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. The phenotype of individuals homozygous or compound heterozygous for this variant is highly specific for cerebral creatine deficiency syndrome based on strict biochemical investigations consistent with disease (PMID: 15651030, 24415674). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cerebral creatine deficiency syndrome. ACMG/AMP Criteria applied: PM3_strong, PM2_supporting, PP3, PS3_supporting, PP4_strong (Richards 2015). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 19, 2024 | This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 45 of the GAMT protein (p.Trp45Arg). This variant is present in population databases (no rsID available, gnomAD 0.005%). This missense change has been observed in individual(s) with cerebral creatine deficiency syndromes and/or guanidinoacetate methyltransferase deficiency (PMID: 23660394, 24415674). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 328352). 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 affects GAMT function (PMID: 24415674). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;.
Vest4
MutPred
Gain of disorder (P = 0.0037);Gain of disorder (P = 0.0037);
MVP
MPC
0.86
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at