NM_000156.6(GAMT):c.59G>C (p.Trp20Ser) AND Deficiency of guanidinoacetate methyltransferase

Germline classification:: Pathogenic (9 submissions)
Last evaluated:: May 25, 2023
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000008801.21

Allele description [Variation Report for NM_000156.6(GAMT):c.59G>C (p.Trp20Ser)]

NM_000156.6(GAMT):c.59G>C (p.Trp20Ser)

Genes:

LOC130062945:ATAC-STARR-seq lymphoblastoid silent region 9707 [Gene]
GAMT:guanidinoacetate N-methyltransferase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.3

Genomic location:

Preferred name:

NM_000156.6(GAMT):c.59G>C (p.Trp20Ser)

Other names:

NM_000156.6(GAMT):c.59G>C

HGVS:

NC_000019.10:g.1401418C>G
NG_009785.1:g.5136G>C
NM_000156.6:c.59G>CMANE SELECT
NM_138924.3:c.59G>C
NP_000147.1:p.Trp20Ser
NP_620279.1:p.Trp20Ser
NC_000019.9:g.1401417C>G
NM_000156.4:c.59G>C
NM_000156.5:c.59G>C
Q14353:p.Trp20Ser

Protein change:

W20S; TRP20SER

Links:

UniProtKB: Q14353#VAR_058102; OMIM: 601240.0003; dbSNP: rs80338734

NCBI 1000 Genomes Browser:

rs80338734

Molecular consequence:

NM_000156.6:c.59G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_138924.3:c.59G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Deficiency of guanidinoacetate methyltransferase (CCDS2)
Synonyms:: CEREBRAL CREATINE DEFICIENCY SYNDROME 2
Identifiers:: MONDO: MONDO:0012999; MedGen: C0574080; Orphanet: 382; OMIM: 612736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000029011	OMIM	no assertion criteria provided	Pathogenic (May 1, 2007)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 15651030, 17336114
SCV000040470	GeneReviews	no classification provided	not provided	unknown	literature only	PubMed (2) [See all records that cite these PMIDs] 15651030, 20301745
SCV000914270	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Apr 5, 2019)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15651030, 16855203, 15108290, 17336114 Citation Link,
SCV001169665	GenomeConnect-Association for Creatine Deficiencies, Association for Creatine Deficiencies	no classification provided	not provided	unknown	phenotyping only
SCV001360425	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 9, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 15651030, 16855203 Citation Link,
SCV001454106	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV002024174	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 12, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004009593	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen_CCDS_ACMG_Specifications_GAMT_v1.1)	Pathogenic (May 25, 2023)	germline	curation	Citation Link,
SCV004198575	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 24, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	phenotyping only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	unknown	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Creatine Deficiency Disorders.

Mercimek-Andrews S, Salomons GS.

2009 Jan 15 [updated 2022 Feb 10]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

PubMed [citation]

PMID:: 20301745

Characterization of seven novel mutations in seven patients with GAMT deficiency.

Item CB, Mercimek-Mahmutoglu S, Battini R, Edlinger-Horvat C, Stromberger C, Bodamer O, Mühl A, Vilaseca MA, Korall H, Stöckler-Ipsiroglu S.

Hum Mutat. 2004 May;23(5):524.

PubMed [citation]

PMID:: 15108290

See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000029011.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In 2 sisters and their male third cousin from a relatively small community in Portugal with cerebral creatine deficiency syndrome-2 (CCDS2; 612736), Caldeira Araujo et al. (2005) identified a homozygous 59G-C transversion in exon 1 of the GAMT gene, resulting in a trp20-to-ser (W20S) substitution.

Almeida et al. (2007) noted that of the 10 reported Portuguese patients with CCDS2, the W20S mutation was found in homozygosity in 8 and in compound heterozygosity in 1. They found that the variant had an overall carrier rate in Portugal of 0.8%, suggesting a founder effect.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneReviews, SCV000040470.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	not provided	not provided	not provided	Assert pathogenicity		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV000914270.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Across a selection of literature, the GAMT c.59G>C (p.Trp20Ser) missense variant has been reported in a homozygous state in at least ten individuals with guanidinoacetate methyltransferase deficiency from six families, and in a compound heterozygous state in at least two additional affected individuals (Item et al. 2004; Caldeira Araujo et al. 2005; Mercimek-Mahmutoglu et al. 2006). In several families, parents of affected individuals homozygous for the p.Trp20Ser variant were found to be heterozygous carriers. Control data are not available for the p.Trp20Ser variant which is reported at a frequency of 0.000109 in the European (non-Finnish) population of the Genome Aggregation Database. GAMT activity was undetectable in lymphoblasts from affected individuals homozygous for the p.Trp20Ser variant (Caldeira Araujo et al. 2005). HeLa cells transfected with p.Trp20Ser variant GAMT showed no increase in GAMT activity in contrast to cells transfected with wild type GAMT where an increase in GAMT activity was demonstrated (Almeida et al. 2007). The p.Trp20Ser variant has been reported at a higher frequency in patients from Portugal. Screening for this variant on newborn blood spot cards in Portugal identified this variant in a heterozygous state in eight newborns (Almeida et al. 2007). A founder effect was suggested based on the results from this study. Based on the collective evidence, the p.Trp20Ser 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GenomeConnect-Association for Creatine Deficiencies, Association for Creatine Deficiencies, SCV001169665.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	phenotyping only	not provided

Description

Variant interpreted as Pathogenic and reported on 07-30-2018 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	validation		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001360425.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: GAMT c.59G>C (p.Trp20Ser) 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 allele was found at a frequency of 5.4e-05 in 74462 control chromosomes. c.59G>C has been reported in the literature in multiple individuals (both homozygous and compound heterozygous) affected with Guanidinoactetate methyltransferase deficiency (e.g. Mercimek-Mahmutoglu_2006, Araujo_2005). In many families it was reported to segregate with the disease (e.g. Mercimek-Mahmutoglu_2006, Araujo_2005). These data indicate that the variant is very likely to be associated with disease. GAMT activity was almost undetectable in patients homozygous for this mutation (Mercimek-Mahmutoglu_2006, Araujo_2005). Two ClinVar submitters (evaluation after 2014) cite the variant as Pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001454106.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002024174.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen, SCV004009593.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The NM_000156.6:c.59G>C variant in GAMT is a missense variant predicted to cause substitution of tryptophan by serine at amino acid 20 (p.Trp20Ser). This variant has been detected in at least 9 unrelated individuals with GAMT deficiency (PMID: 15651030, PMID: 16855203, PMID: 15108290). Of those individuals, one was compound heterozygous for the variant and a pathogenic variant, c.521G>A (p.Trp174*, in trans (PMID: 16855203) and eight individuals were homozygous for the variant (PMID: 15651030, PMID: 16855203, PMID: 15108290) (2 points total) (PM3_Strong). These individuals showed elevated plasma GAA and urine GAA (PMID: 15651030, PMID: 16855203, PMID: 15108290), three also showed deficient (<5% wild-type) GAMT enzyme activity in lymphoblasts (PMID: 15651030), and one also showed deficient (<5% wild-type) GAMT enzyme activity in fibroblasts and reduced creatine signal on brain MRS (PMID: 16855203, PMID: 21140503) (PP4_Strong). Expression of the variant in HeLa cells resulted in 3% wild type GAMT activity indicating that this variant may impact protein function (PMID: 17336114)(PS3_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001 (3/27420 alleles) in the European (non-Finnish) population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004); however, as this variant is covered in <50% of individuals in gnomAD v2.1.1, allele frequency estimates may not be reliable and thus PM2_Supporting is not met. The computational predictor REVEL gives a score of 0.94 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3). There is a ClinVar entry for this variant (Variation ID: 8303, 2 star review status) with 9 submitters classifying the variant as pathogenic and 1 submitter classifying the variant as likely 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 1.1.0): PS3_Supporting, PM3_Strong, PP3, PP4_Strong. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 25, 2023)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004198575.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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