rs200833152

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1BS3_Supporting

This summary comes from the ClinGen Evidence Repository: NM_000156.6:c.79T>C variant in GAMT is a missense variant that is predicted to result in the substitution of tyrosine by histidine at amino acid 27 (p.Tyr27His). This variant was identified in the homozygous state in an individual with normal GAMT enzyme activity in fibroblasts (PMID:24415674). The variant is present in gnomAD v2.1.1. at a maximum population frequency of 0.00471 (>0.003, cutoff for BA1) and found in the homozygous state in 2 individuals in gnomAD v2.1.1 (BA1). In fibroblasts, overexpressing the GAMT c.79T>C (p.Tyr27His) variant, restored GAMT activity to similar levels as the wild-type GAMT transfection (PMID:24415674)(BS3_Supporting). There is a ClinVar entry for this variant (Variation ID: 167131). In summary, this variant meets the criteria to be classified as benign for GAMT deficiency. GAMT-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Cerebral Creatine Deficiencies VCEP (Specifications Version 1.1.0): BA1, BS3_Supporting.(Classification approved by the ClinGen CCDS VCEP on February 8, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA295620/MONDO:0012999/026

Frequency

Genomes: 𝑓 0.0034 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0046 ( 18 hom. )

Consequence

GAMT
NM_000156.6 missense

Scores

Clinical Significance

Benign reviewed by expert panel P:1U:3B:14O:1

Conservation

PhyloP100: 7.08

Publications

13 publications found

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 Gene-Disease associations (from GenCC):

guanidinoacetate methyltransferase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics

GAMT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BS3

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAMT	NM_000156.6 link	c.79T>C	p.Tyr27His	missense_variant	Exon 1 of 6	ENST00000252288.8	NP_000147.1
GAMT	NM_138924.3 link	c.79T>C	p.Tyr27His	missense_variant	Exon 1 of 5		NP_620279.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
GAMT	ENST00000252288.8 link	c.79T>C	p.Tyr27His	missense_variant	Exon 1 of 6	1	NM_000156.6	ENSP00000252288.1
GAMT	ENST00000447102.8 link	c.79T>C	p.Tyr27His	missense_variant	Exon 1 of 5	2		ENSP00000403536.2
GAMT	ENST00000640762.1 link	c.79T>C	p.Tyr27His	missense_variant	Exon 1 of 6	5		ENSP00000492031.1

Frequencies

GnomAD3 genomes

AF:

0.00339

AC:

516

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00159

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00582

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000566

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00494

Gnomad OTH

AF:

0.00766

GnomAD2 exomes

AF:

0.00282

AC:

245

AN:

86858

AF XY:

0.00268

show subpopulations

Gnomad AFR exome

AF:

0.00160

Gnomad AMR exome

AF:

0.00477

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000970

Gnomad NFE exome

AF:

0.00444

Gnomad OTH exome

AF:

0.00376

GnomAD4 exome

AF:

0.00456

AC:

5989

AN:

1313380

Hom.:

Cov.:

AF XY:

0.00438

AC XY:

2834

AN XY:

647264

show subpopulations

African (AFR)

AF:

0.00130

AC:

AN:

26962

American (AMR)

AF:

0.00455

AC:

123

AN:

27058

Ashkenazi Jewish (ASJ)

AF:

0.000430

AC:

AN:

23234

East Asian (EAS)

AF:

0.00

AC:

AN:

28760

South Asian (SAS)

AF:

0.00

AC:

AN:

70922

European-Finnish (FIN)

AF:

0.00136

AC:

AN:

33100

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4324

European-Non Finnish (NFE)

AF:

0.00532

AC:

5557

AN:

1044644

Other (OTH)

AF:

0.00403

AC:

219

AN:

54376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

323

646

968

1291

1614

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

228

456

684

912

1140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00339

AC:

516

AN:

152132

Hom.:

Cov.:

AF XY:

0.00333

AC XY:

248

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.00159

AC:

AN:

41532

American (AMR)

AF:

0.00582

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5140

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000566

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00495

AC:

336

AN:

67942

Other (OTH)

AF:

0.00758

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

123

154

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00519

Hom.:

Bravo

AF:

0.00357

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00623

AC:

ESP6500AA

AF:

0.00123

AC:

ESP6500EA

AF:

0.00239

AC:

ExAC

AF:

0.00165

AC:

164

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Uncertain:3Benign:14Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:4

Feb 20, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 15, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Sep 16, 2014

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 13, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: GAMT c.79T>C (p.Tyr27His) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0028 in 86858 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in GAMT causing Cerebral Creatine Deficiency Syndrome 2 phenotype (0.0011), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.79T>C in individuals affected with Cerebral Creatine Deficiency Syndrome 2 and no experimental evidence demonstrating its impact on protein function have been reported. 11 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely pathogenic n=1, VUS n=2, likely benign n=3, benign n=5). Based on the evidence outlined above, the variant was classified as benign. -

not provided

Uncertain:1Benign:4

Apr 29, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GAMT: PP3, BS2 -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 19, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Deficiency of guanidinoacetate methyltransferase

Pathogenic:1Uncertain:1Benign:2

Apr 01, 2020

Elsea Laboratory, Baylor College of Medicine

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Feb 08, 2023

ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

NM_000156.6:c.79T>C variant in GAMT is a missense variant that is predicted to result in the substitution of tyrosine by histidine at amino acid 27 (p.Tyr27His). This variant was identified in the homozygous state in an individual with normal GAMT enzyme activity in fibroblasts (PMID: 24415674). The variant is present in gnomAD v2.1.1. at a maximum population frequency of 0.00471 (>0.003, cutoff for BA1) and found in the homozygous state in 2 individuals in gnomAD v2.1.1 (BA1). In fibroblasts, overexpressing the GAMT c.79T>C (p.Tyr27His) variant, restored GAMT activity to similar levels as the wild-type GAMT transfection (PMID: 24415674)(BS3_Supporting). There is a ClinVar entry for this variant (Variation ID: 167131). In summary, this variant meets the criteria to be classified as benign for GAMT deficiency. GAMT-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Cerebral Creatine Deficiencies VCEP (Specifications Version 1.1.0): BA1, BS3_Supporting. (Classification approved by the ClinGen CCDS VCEP on February 8, 2023). -

Jan 11, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Nov 03, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Cerebral creatine deficiency syndrome

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Intellectual disability

Benign:1

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

GAMT-related disorder

Benign:1

Jan 22, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Guanidinoacetate methyltransferase (GAMT) deficiency

Other:1

GenomeConnect-Association for Creatine Deficiencies, Association for Creatine Deficiencies

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Uncertain significance and reported on 08-22-2014 by GTR ID 26957. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect facilitates ClinVar submission from the Association for Creatine Deficiencies registry and does not attempt to reinterpret the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

D;.;.

Eigen

Uncertain

0.35

Eigen_PC

Benign

0.18

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.78

T;T;T

M_CAP

Pathogenic

0.68

MetaRNN

Benign

0.0093

T;T;T

MetaSVM

Uncertain

0.63

MutationAssessor

Pathogenic

3.0

M;.;M

PhyloP100

7.1

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-2.5

N;.;N

REVEL

Pathogenic

0.65

Sift

Pathogenic

0.0

D;.;D

Sift4G

Pathogenic

0.0

D;.;D

Polyphen

1.0

D;.;.

Vest4

0.52

MVP

0.91

MPC

0.72

ClinPred

0.066

GERP RS

3.1

PromoterAI

-0.28

Neutral

(source)

Varity_R

0.62

gMVP

0.80

Mutation Taster

=85/15

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over