rs374724533

Positions:

• chr19-1399180-G-A
• chr19-1399180-G-C
• chr19-1399180-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP4_Strong PM3 PP3_Moderate PS3_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000156.6:c.407C>T variant in GAMT is a missense variant predicted to cause substitution of threonine by methionine at amino acid 136 (p.Thr136Met). This variant has been detected in 3 unrelated individuals with GAMT deficiency (PMID:24415674, PMID:21140503, ClinVar SCV001428825.1). Of those individuals, two were compound heterozygous for the variant and a pathogenic variant, c.316C>T (p.Q106*) in unknown phase (PMID:24415674, PMID:21140503) and 1 was homozygous for the variant (ClinVar SCV001428825.1) (1.5pts total, PM3). One of these individuals had elevated GAA in plasma, deficient GAMT enzyme activity (<5% wild-type enzyme) in fibroblasts, and significantly reduced creatine peak on brain MRS (PMID:21140503) and one individual had an absent creatine peak with visible GAA peak on brain MRS (PMID:24415674) (PP4_Strong). Expression of the variant in GAMT-deficient fibroblasts resulted in <5% wild type GAMT activity indicating that this variant may impact protein function (PMID:24415674)(PS3_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000009 (1/113420 alleles) 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). The computational predictor REVEL gives a score of 0.976 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3_Moderate). There is a ClinVar entry for this variant (Variation ID: 544257). 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): PP4_Strong, PM3, PP3_Moderate, PS3_Supporting, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on Oct. 2026, 2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA9043669/MONDO:0012999/026

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: GAMT NM_000156.6 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:8 O:1
• Conservation: PhyloP100: 7.97

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 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.407C>T	p.Thr136Met	missense_variant	4/6	ENST00000252288.8	NP_000147.1
GAMT	NM_138924.3	c.407C>T	p.Thr136Met	missense_variant	4/5		NP_620279.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAMT	ENST00000252288.8	c.407C>T	p.Thr136Met	missense_variant	4/6	1	NM_000156.6	ENSP00000252288.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 33

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251062 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135864

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: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461332 Hom.: 0 Cov.: 34 AF XY: 0.0000138 AC XY: 10 AN XY: 726992

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74346

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Deficiency of guanidinoacetate methyltransferase Pathogenic:5 Other:1

Pathogenic, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Oct 26, 2023	The NM_000156.6:c.407C>T variant in GAMT is a missense variant predicted to cause substitution of threonine by methionine at amino acid 136 (p.Thr136Met). This variant has been detected in 3 unrelated individuals with GAMT deficiency (PMID: 24415674, PMID: 21140503, ClinVar SCV001428825.1). Of those individuals, two were compound heterozygous for the variant and a pathogenic variant, c.316C>T (p.Q106*) in unknown phase (PMID: 24415674, PMID: 21140503) and 1 was homozygous for the variant (ClinVar SCV001428825.1) (1.5pts total, PM3). One of these individuals had elevated GAA in plasma, deficient GAMT enzyme activity (<5% wild-type enzyme) in fibroblasts, and significantly reduced creatine peak on brain MRS (PMID: 21140503) and one individual had an absent creatine peak with visible GAA peak on brain MRS (PMID: 24415674) (PP4_Strong). Expression of the variant in GAMT-deficient fibroblasts resulted in <5% wild type GAMT activity indicating that this variant may impact protein function (PMID: 24415674)(PS3_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000009 (1/113420 alleles) 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). The computational predictor REVEL gives a score of 0.976 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3_Moderate). There is a ClinVar entry for this variant (Variation ID: 544257). 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): PP4_Strong, PM3, PP3_Moderate, PS3_Supporting, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on Oct. 2026, 2023) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 06, 2021	- -
not provided, no classification provided	phenotyping only	GenomeConnect-Association for Creatine Deficiencies, Association for Creatine Deficiencies	-	Variant interpreted as Likely pathogenic and reported on 04-18-2018 by lab or GTR ID MedGenome. GenomeConnect - Association for Creatine Deficiencies assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 07, 2019	This variant was identified as homozygous -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 11, 2024	- -

Cerebral creatine deficiency syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 136 of the GAMT protein (p.Thr136Met). This variant is present in population databases (rs374724533, gnomAD 0.0009%). This missense change has been observed in individual(s) with guanidinoacetate methyltransferase (GAMT) deficiency (PMID: 19892372, 24415674; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 544257). 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 expected to disrupt GAMT protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GAMT function (PMID: 24415674). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Nov 02, 2021	The p.Thr136Met variant in GAMT has been reported in 3 individuals with cerebral creatine deficiency syndrome (PMID: 19892372, 24415674, ClinVar) and has been identified in 0.0009% (1/113420) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs374724533). 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#: 544257) and has been interpreted as likely pathogenic by Institute of Human Genetics (University of Leipzig Medical Center), Invitae, and Natera, Inc., and as pathogenic by GeneDx. Of the 3 affected individuals, 1 of those were homozygote, and 2 were compound heterozygotes that carried a reported likely pathogenic variant with unknown phase, which increases the likelihood that the p.Thr136Met variant is pathogenic (PMID: 19892372, 24415674, ClinVar). In vitro functional studies provide some evidence that the p.Thr136Met 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, though this information is not predictive enough to determine pathogenicity. The phenotype of individuals compound heterozygous for this variant is highly specific for cerebral creatine deficiency syndrome based on strict biochemical investigations consistent with disease (PMID: 19892372, 24415674). 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: PP4_strong, PM3, PS3_supporting, PM2_supporting, PP3 (Richards 2015). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 20, 2024

Published functional studies found this variant is associated with significantly reduced GAMT activity (PMID: 24415674); 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: 21140503, 19892372, 26003046, 24415674, 38020815, 39006040) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;.;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;.;H
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.4	D;.;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.0060	D;.;D
Polyphen		1.0	D;.;.
Vest4		0.92
MVP		0.99
MPC		0.65
ClinPred		1.0	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.71
gMVP		0.84

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

Other links and lift over

dbSNP: rs374724533; hg19: chr19-1399179;