rs80338734

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3PM2_SupportingPM5

This summary comes from the ClinGen Evidence Repository: The NM_000156.6:c.59G>T variant in GAMT is a missense variant that is predicted to result in the substitution of tryptophan by leucine at amino acid 20 (p.Trp20Leu). To our knowledge, this variant has not been reported in individuals with GAMT deficiency and the result of functional studies are not available. The computational predictor REVEL gives a score of 0.804 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3). Another missense variant, c.59G>C (p.Trp20Ser) (ClinVar Variation ID: 8303)) has been reported at the same amino acid position and has been classified as pathogenic for GAMT deficiency by the ClinGen CCDS VCEP (PM5). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 588631, 1 star review status). In summary, this variant meets the criteria to be classified as uncertain significance 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): PM2_Supporting, PM5, PP3.(Classification approved by the ClinGen CCDS VCEP, Sept 12, 2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA402998326/MONDO:0012999/026

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

GAMT
NM_000156.6 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:3

Conservation

PhyloP100: 7.44

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 Uncertain_significance. Variant got 4 ACMG points.

PM2

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

PM5

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

PP3

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.59G>T	p.Trp20Leu	missense_variant	Exon 1 of 6	ENST00000252288.8	NP_000147.1	Q14353-1V9HWB2
GAMT	NM_138924.3 link	c.59G>T	p.Trp20Leu	missense_variant	Exon 1 of 5		NP_620279.1	Q14353-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GAMT	ENST00000252288.8 link	c.59G>T	p.Trp20Leu	missense_variant	Exon 1 of 6	1	NM_000156.6	ENSP00000252288.1	Q14353-1
GAMT	ENST00000447102.8 link	c.59G>T	p.Trp20Leu	missense_variant	Exon 1 of 5	2		ENSP00000403536.2	Q14353-2
GAMT	ENST00000640762.1 link	c.59G>T	p.Trp20Leu	missense_variant	Exon 1 of 6	5		ENSP00000492031.1	A0A1W2PR36

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000100

AC:

AN:

1296552

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

638052

show subpopulations

Gnomad4 AFR exome

AF:

0.000113

Gnomad4 AMR exome

AF:

0.0000399

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000435

Gnomad4 FIN exome

AF:

0.0000308

Gnomad4 NFE exome

AF:

0.00000483

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152086

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Inborn genetic diseases

Pathogenic:1

Jan 05, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.W20L variant (also known as c.59G>T), located in coding exon 1 of the GAMT gene, results from a G to T substitution at nucleotide position 59. The tryptophan at codon 20 is replaced by leucine, an amino acid with similar properties. One disease-causing mutation, p.W20S, has been described in the same codon. Based on internal structural assessment, this alteration will weaken binding of the substrate S-adenosyl-methinine, impairing protein function {Unpublished structure - PDB: 3ORH}. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not specified

Uncertain:1

Oct 27, 2022

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GAMT c.59G>T (p.Trp20Leu) results in a non-conservative amino acid change located in the Arginine N-methyltransferase 2-like domain (IPR026480) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 74462 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.59G>T in individuals affected with Cerebral Creatine Deficiency Syndrome 2 and no experimental evidence demonstrating its impact on protein function have been reported. Another variant in the same (highly conserved) nucleotide and amino acid residue (c.59G>C, p.Trp20Ser) is classified as pathogenic by our laboratory, providing moderate evidence of pathogenicity for c.59G>T. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Cerebral creatine deficiency syndrome

Uncertain:1

Aug 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tryptophan, which is neutral and slightly polar, with leucine, which is neutral and non-polar, at codon 20 of the GAMT protein (p.Trp20Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GAMT-related conditions. ClinVar contains an entry for this variant (Variation ID: 588631). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Trp20 amino acid residue in GAMT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15651030, 16855203, 17336114). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Deficiency of guanidinoacetate methyltransferase

Uncertain:1

Sep 13, 2023

ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000156.6:c.59G>T variant in GAMT is a missense variant that is predicted to result in the substitution of tryptophan by leucine at amino acid 20 (p.Trp20Leu). To our knowledge, this variant has not been reported in individuals with GAMT deficiency and the result of functional studies are not available. The computational predictor REVEL gives a score of 0.804 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3). Another missense variant, c.59G>C (p.Trp20Ser) (ClinVar Variation ID: 8303)) has been reported at the same amino acid position and has been classified as pathogenic for GAMT deficiency by the ClinGen CCDS VCEP (PM5). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 588631, 1 star review status). In summary, this variant meets the criteria to be classified as uncertain significance 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): PM2_Supporting, PM5, PP3. (Classification approved by the ClinGen CCDS VCEP, Sept 12, 2023) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.84

D;.;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.77

T;T;T

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.86

D;D;D

MetaSVM

Uncertain

0.76

MutationAssessor

Pathogenic

3.1

M;.;M

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-5.8

D;.;D

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0070

D;.;D

Sift4G

Uncertain

0.037

D;.;D

Polyphen

1.0

D;.;.

Vest4

0.72

MutPred

0.54

Loss of catalytic residue at W20 (P = 0.0221);Loss of catalytic residue at W20 (P = 0.0221);Loss of catalytic residue at W20 (P = 0.0221);

MVP

0.95

MPC

0.84

ClinPred

1.0

GERP RS

4.0

Varity_R

0.94

gMVP

0.77

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