rs749390953

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM3PP4_StrongPM2_SupportingPVS1_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000156.6:c.491del (p.Gly164AlafsTer14) variant in GAMT is a frameshift variant predicted to cause a premature stop codon in the last 50 nucleotides of the penultimate exon and therefore to escape nonsense mediated decay. More than 10% of the protein is predicted to be removed. (PVS1_Strong). This variant has been detected in in 7 unrelated individuals with GAMT deficiency, all of whom were homozygous for the variant (PMID:29302074, PMID:32214227, PMID:15234333, PMID:23660394, PMID:15108290) (1pt, PM3). One of these individuals had elevated GAA in plasma, elevated GAA in urine, deficient GAMT enzyme activity (<5% wild-type) in fibroblasts, and significantly reduced creatine peak with present GAA peak on brain MRS (PMID:15234333) and one of these individuals had elevated urine GAA and undetectable GAMT enzyme activity in fibroblasts (PMID:15108290) (PP4_Strong). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001607 (4/24886 alleles) in the African/African American population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 810628, 2 star review status) with 7 submitters classifying the variant as pathogenic. 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 1.0): PVS1_Strong, PM2_Supporting, PM3, PP4_Strong. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 25, 2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA9043627/MONDO:0012999/026

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

GAMT
NM_000156.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:10

Conservation

PhyloP100: 5.84

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 11 ACMG points.

PVS1

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.

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 linkuse as main transcript	c.491del	p.Gly164AlafsTer14	frameshift_variant	5/6	ENST00000252288.8	NP_000147.1
GAMT	NM_138924.3 linkuse as main transcript	c.491del	p.Gly164AlafsTer14	frameshift_variant	5/5		NP_620279.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAMT	ENST00000252288.8 linkuse as main transcript	c.491del	p.Gly164AlafsTer14	frameshift_variant	5/6	1	NM_000156.6	ENSP00000252288	P1	Q14353-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250692

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135780

show subpopulations

Gnomad AFR exome

AF:

0.000185

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461126

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726868

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Deficiency of guanidinoacetate methyltransferase

Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 07, 2020	- -
Pathogenic, no assertion criteria provided	research	Section for Clinical Neurogenetics, University of Tübingen	Aug 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 21, 2021	Variant summary: GAMT c.491delG (p.Gly164AlafsX14) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.2e-05 in 250692 control chromosomes. c.491delG has been reported in the literature in multiple individuals affected with Guanidinoactetate Methyltransferase Deficiency (example, Item_2004, Hengel_2020, Mercimek-Mahmutoglu_2006, Comeaux_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Apr 22, 2024	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	May 25, 2023	The NM_000156.6:c.491del (p.Gly164AlafsTer14) variant in GAMT is a frameshift variant predicted to cause a premature stop codon in the last 50 nucleotides of the penultimate exon and therefore to escape nonsense mediated decay. More than 10% of the protein is predicted to be removed. (PVS1_Strong). This variant has been detected in in 7 unrelated individuals with GAMT deficiency, all of whom were homozygous for the variant (PMID: 29302074, PMID: 32214227, PMID: 15234333, PMID: 23660394, PMID: 15108290) (1pt, PM3). One of these individuals had elevated GAA in plasma, elevated GAA in urine, deficient GAMT enzyme activity (<5% wild-type) in fibroblasts, and significantly reduced creatine peak with present GAA peak on brain MRS (PMID: 15234333) and one of these individuals had elevated urine GAA and undetectable GAMT enzyme activity in fibroblasts (PMID: 15108290) (PP4_Strong). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001607 (4/24886 alleles) in the African/African American population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 810628, 2 star review status) with 7 submitters classifying the variant as pathogenic. 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 1.0): PVS1_Strong, PM2_Supporting, PM3, PP4_Strong. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 25, 2023) -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 06, 2023	- -

Cerebral creatine deficiency syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Nov 02, 2021	The p.Gly164fs variant in GAMT has been reported in at least 6 individuals with cerebral creatine deficiency syndrome (PMID: 15108290, 32214227, 16855203, 23660394), and has been identified in in 0.02% (4/24886) of African/African-American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs768985121). 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 6 affected individuals, all of those were homozygotes, which increases the likelihood that the p.Gly164fs variant is pathogenic (PMID: 15108290, 32214227, 16855203, 23660394). This variant has also been reported in ClinVar (Variation ID#: 810628) and has been interpreted as pathogenic by Section for Clinical Neurogenetics (University of Tübingen) and Women's Health and Genetics (Laboratory Corporation of America, LabCorp). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 164 and leads to a premature termination codon 14 amino acids downstream. This termination codon occurs within the terminal 50 bases of the second to last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the GAMT gene is an established disease mechanism in autosomal recessive cerebral creatine deficiency syndrome. The phenotype of individuals homozygous for this variant is highly specific for cerebral creatine deficiency syndrome based on strict biochemical investigations consistent with disease (PMID: 23660394, 15108290). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cerebral creatine deficiency syndrome. ACMG/AMP Criteria applied: PVS1_strong, PM3, PP4_strong, PM2_supporting (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.491del;p.(Gly164Alafs14) is a null frameshift variant (NMD) in the GAMT gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevantexon to the transcript -PVS1_strong. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 810628; PMID: 32214227; 23660394; 16855203) - PS4. The variant is present at low allele frequencies population databases (rs749390953– gnomAD 0.003942%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Gly164Alafs14) was detected in trans with a pathogenic variant (PMID: 16855203) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	This sequence change creates a premature translational stop signal (p.Gly164Alafs14) in the GAMT gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 73 amino acid(s) of the GAMT protein. This variant is present in population databases (rs749390953, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with guanidinoacetate methyltransferase (GAMT) deficiency (PMID: 15108290, 23660394). ClinVar contains an entry for this variant (Variation ID: 810628). This variant disrupts a region of the GAMT protein in which other variant(s) (p.Trp174) have been determined to be pathogenic (PMID: 17171576, 19027335, 23660394, 24268530). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 28, 2022

Frameshift variant predicted to result in protein truncation, as the last 73 amino acids are replaced with 13 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 15234333, 23660394, 19027335, 26003046, 16054853, 15108290, 29302074, 32214227) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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