rs374724533

chr19-1399180-G-Achr19-1399180-G-Cchr19-1399180-G-T

Variant summary

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

The NM_000156.6(GAMT):c.407C>T(p.Thr136Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. T136T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

GAMT
NM_000156.6 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:8O:1

Conservation

PhyloP100: 7.97

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 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000156.6

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.968

PP5

Variant 19-1399180-G-A is Pathogenic according to our data. Variant chr19-1399180-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 544257.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-1399180-G-A 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.407C>T	p.Thr136Met	missense_variant	4/6	ENST00000252288.8
GAMT	NM_138924.3 linkuse as main transcript	c.407C>T	p.Thr136Met	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAMT	ENST00000252288.8 linkuse as main transcript	c.407C>T	p.Thr136Met	missense_variant	4/6	1	NM_000156.6	P1	Q14353-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152202

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251062

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135864

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:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461332

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726992

show subpopulations

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:

AN:

152202

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74346

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Deficiency of guanidinoacetate methyltransferase

Pathogenic:5Other:1

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 -
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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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) -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 17, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 06, 2021	- -

Cerebral creatine deficiency syndrome

Pathogenic:2

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). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 10, 2022

Published functional studies demonstrate a damaging effect, specifically GAMT enzyme activity was very low in homogenates from cells overexpressing T136M (Mercimek-Mahmutoglu et al., 2014); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21140503, 19892372, 26003046, 24415674) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.53

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

D;.;.

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Pathogenic

0.76

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.8

H;.;H

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.65

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

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

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