19-1398964-C-T

Position:

chr19-1398964-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP4_StrongPM3PVS1_StrongPM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000156.6:c.522G>A (p.Trp174Ter) variant is a nonsense variant in the last 50bp of the penultimate exon of GAMT, predicted to cause a premature stop codon in the last 50 nucleotides of the penultimate exon of the gene and therefore to escape nonsense mediated decay. More than 10% of the protein is predicted to be removed (PVS1_Strong). At least six probands and two siblings have been reported with clinical and biochemical features consistent with GAMT deficiency including 3 probands and one sibling with elevated plasma GAA (PMID 23660394, https://adc.bmj.com/content/103/2/e1.24), 1 proband with enzyme deficiency (PMID 17171576), 2 probands with reduced plasma creatine, elevated plasma GAA, and reduced creatine peak on MRS (PMID 23583224, 24071436), and a sibling of one of these patients with reduced plasma creatine and elevated plasma GAA (PMID 23583224) (PP4_Strong). Of these probands 4 are compound heterozygous for the variant and a variant that is classified as pathogenic by the ClinGen CCDS VCEP, c.327G>A, phase unknown (PMIDs 17171576, 19027335, 23583224, 23660394, 24071436, 24268530, https://adc.bmj.com/content/103/2/e1.24 (PM3). Another two probands are compound heterozygous for the variant and a missense variant, either c.491G>A (p.Gly164Asp) or c.505T>C (p.Cys169Arg) (PMID 23660394, 24268530). The in trans data from these patients will be used in the assessment of the missense variants and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 (7/113306 alleles) in the European non-Finnish population, which is less that 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: 205584). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1_Strong, PP4_Strong, PM3, PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA314812/MONDO:0012999/026

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

GAMT
NM_000156.6 stop_gained

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:12O:1

Conservation

PhyloP100: 5.81

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:

GAMT (HGNC:):

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.522G>A	p.Trp174*	stop_gained	5/6	ENST00000252288.8	NP_000147.1	Q14353-1V9HWB2
GAMT	NM_138924.3 linkuse as main transcript	c.522G>A	p.Trp174*	stop_gained	5/5		NP_620279.1	Q14353-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAMT	ENST00000252288.8 linkuse as main transcript	c.522G>A	p.Trp174*	stop_gained	5/6	1	NM_000156.6	ENSP00000252288.1		Q14353-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152192

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

250890

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135826

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:

0.0000618

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000152

AC:

222

AN:

1461130

Hom.:

Cov.:

AF XY:

0.000154

AC XY:

112

AN XY:

726870

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000447

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:

0.000192

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74346

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:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000655

Hom.:

Bravo

AF:

0.0000604

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Deficiency of guanidinoacetate methyltransferase

Pathogenic:8Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 20, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The GAMT c.522G>A (p.Trp174Ter) variant has been reported in at least six studies and is found in at least eight individuals with guanidinoacetate methyltransferase (GAMT) deficiency in a compound heterozygous state, including one affected sibling pair (Verhoeven et al. 2005; Morris et al. 2007; Dhar et al. 2009; Viau et al. 2013; El-Gharbawy et al. 2013; Comeaux et al. 2013). Across the studies, individuals displayed a biochemical profile consistent with GAMT deficiency including decreased creatine and elevated guanidinoacetate (GAA) levels in urine or serum as compared to controls or laboratory reference values. Additionally, Morris et al. (2007) demonstrated no detectable GAMT activity in individual fibroblasts. Control data are unavailable for this variant, which is reported at a frequency of 0.00006 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence and due to the potential impact of stop-gained variants, the p.Trp174Ter variant is classified as pathogenic for guanidinoacetate methyltransferase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 30, 2021	- -
not provided, no classification provided	phenotyping only	GenomeConnect-Association for Creatine Deficiencies, Association for Creatine Deficiencies	-	Variant interpreted as Pathogenic and reported on 12-08-2009 by GTR ID 1006. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 22, 2018	Variant summary: GAMT c.522G>A (p.Trp174X) 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. The variant allele was found at a frequency of 2.8e-05 in 246008 control chromosomes (gnomAD). c.522G>A has been reported in the literature in multiple individuals affected with creatine deficiency syndromes and Guanidinoactetate methyltransferase deficiency. 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. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 31, 2019	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Jun 06, 2022	The NM_000156.6:c.522G>A (p.Trp174Ter) variant is a nonsense variant in the last 50bp of the penultimate exon of GAMT, predicted to cause a premature stop codon in the last 50 nucleotides of the penultimate exon of the gene and therefore to escape nonsense mediated decay. More than 10% of the protein is predicted to be removed (PVS1_Strong). At least six probands and two siblings have been reported with clinical and biochemical features consistent with GAMT deficiency including 3 probands and one sibling with elevated plasma GAA (PMID 23660394, https://adc.bmj.com/content/103/2/e1.24), 1 proband with enzyme deficiency (PMID 17171576), 2 probands with reduced plasma creatine, elevated plasma GAA, and reduced creatine peak on MRS (PMID 23583224, 24071436), and a sibling of one of these patients with reduced plasma creatine and elevated plasma GAA (PMID 23583224) (PP4_Strong). Of these probands 4 are compound heterozygous for the variant and a variant that is classified as pathogenic by the ClinGen CCDS VCEP, c.327G>A, phase unknown (PMIDs 17171576, 19027335, 23583224, 23660394, 24071436, 24268530, https://adc.bmj.com/content/103/2/e1.24 (PM3). Another two probands are compound heterozygous for the variant and a missense variant, either c.491G>A (p.Gly164Asp) or c.505T>C (p.Cys169Arg) (PMID 23660394, 24268530). The in trans data from these patients will be used in the assessment of the missense variants and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 (7/113306 alleles) in the European non-Finnish population, which is less that 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: 205584). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PVS1_Strong, PP4_Strong, PM3, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022). -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 23, 2022	- -

Cerebral creatine deficiency syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Nov 02, 2021	The p.Trp174Ter (c.522G>A) variant in GAMT has been reported in at least 6 individuals with cerebral creatine deficiency syndrome (PMID: 19027335, 23660394, 24071436, 24268530) and has been identified in in 0.006% (7/113306) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs370421531). 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 at least 6 affected individuals, 3 were compound heterozygotes that carried a reported pathogenic variant with unknown phase, which increases the likelihood that the p.Trp174Ter variant is pathogenic (Variation ID: 21065, 205581; PMID: 19027335, 23660394, 24071436, 24268530). This variant has also been reported in ClinVar (Variation ID#: 205584) and has been interpreted as pathogenic by Fulgent Genetics, GeneDx, Illumina Clinical Services Laboratory (Illumina), Women's Health and Genetics (Laboratory Corporation of America, LabCorp), Invitae, and Natera, Inc. This nonsense variant leads to a premature termination codon at position 174. This alteration 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 or compound heterozygous for this variant is highly specific for cerebral creatine deficiency syndrome based on strict biochemical investigations consistent with disease (PMID: 23660394, 24071436, 19027335). 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, PM2_supporting, PP4_strong (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	This sequence change creates a premature translational stop signal (p.Trp174*) in the GAMT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAMT are known to be pathogenic (PMID: 15108290). This variant is present in population databases (rs370421531, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with guanidinoacetate methyltransferase deficiency (PMID: 17171576, 19027335, 23583224, 23660394, 24071436, 24268530). ClinVar contains an entry for this variant (Variation ID: 205584). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 06, 2022

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 63 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 17171576, 19027335, 15108290, 24071436, 23583224, 24268530, 23660394, 16169544, 26003046, 34389248) -

GAMT-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2023

The GAMT c.522G>A variant is predicted to result in premature protein termination (p.Trp174*). This variant was reported in the compound heterozygous in multiple individuals with guanidinoacetate methyltransferase deficiency (see, for example, Morris et al. 2007. PubMed ID: 17171576; Dhar et al. 2008. PubMed ID: 19027335). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-1398963-C-T). Nonsense variants in GAMT are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.98

Vest4

0.96

GERP RS

4.0

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