rs886054247

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000156.6(GAMT):c.133T>A(p.Trp45Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000735 in 1,538,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000076 ( 0 hom. )

Consequence

GAMT
NM_000156.6 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:6

Conservation

PhyloP100: 8.92

Variant links:

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]

GAMT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000156.6

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.973

PP5

Variant 19-1401344-A-T is Pathogenic according to our data. Variant chr19-1401344-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 328352.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-1401344-A-T is described in Lovd as [Pathogenic]. Variant chr19-1401344-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAMT	NM_000156.6 linkuse as main transcript	c.133T>A	p.Trp45Arg	missense_variant	1/6	ENST00000252288.8
GAMT	NM_138924.3 linkuse as main transcript	c.133T>A	p.Trp45Arg	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAMT	ENST00000252288.8 linkuse as main transcript	c.133T>A	p.Trp45Arg	missense_variant	1/6	1	NM_000156.6	P1	Q14353-1
GAMT	ENST00000447102.8 linkuse as main transcript	c.133T>A	p.Trp45Arg	missense_variant	1/5	2			Q14353-2
GAMT	ENST00000640762.1 linkuse as main transcript	c.112+21T>A		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000461

AC:

AN:

152002

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000249

AC:

AN:

160944

Hom.:

AF XY:

0.0000110

AC XY:

AN XY:

91176

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000543

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000765

AC:

106

AN:

1386396

Hom.:

Cov.:

AF XY:

0.0000668

AC XY:

AN XY:

688466

show subpopulations

Gnomad4 AFR exome

AF:

0.0000344

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000951

Gnomad4 OTH exome

AF:

0.0000348

GnomAD4 genome

AF:

0.0000461

AC:

AN:

152002

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74262

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000378

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	Baylor Genetics	Oct 08, 2023	- -
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) -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 02, 2022	- -

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	Invitae	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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.49

Cadd

Pathogenic

Dann

Uncertain

0.99

DEOGEN2

Pathogenic

0.92

D;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.77

T;T

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

3.8

H;H

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-12

D;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.98

MutPred

0.83

Gain of disorder (P = 0.0037);Gain of disorder (P = 0.0037);

MVP

1.0

MPC

0.86

ClinPred

1.0

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.96

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over