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

Clinical significance:Pathogenic (Last evaluated: Dec 9, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
6 submissions [Details]
Record status:
current
Accession:
RCV000008801.9

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

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

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)
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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000029011OMIMno assertion criteria providedPathogenic
(May 1, 2007)
germlineliterature only

PubMed (2)
[See all records that cite these PMIDs]

SCV000040470GeneReviewsno assertion criteria providedpathologic
(Aug 18, 2011)
not providedcuration

SCV000914270Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Pathogenic
(Apr 5, 2019)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV001169665GenomeConnect-Association for Creatine Deficiencies, Association for Creatine Deficienciesno assertion providednot providedunknownphenotyping only

SCV001360425Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Dec 9, 2019)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV001454106Natera, Inc.no assertion criteria providedPathogenic
(Sep 16, 2020)
germlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedunknownyesnot providednot providednot providednot providednot providedphenotyping only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providednot providednot providednot providednot providednot providednot providednot providedcuration

Citations

PubMed

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

A prevalent pathogenic GAMT mutation (c.59G>C) in Portugal.

Almeida LS, Vilarinho L, Darmin PS, Rosenberg EH, Martinez-Muñoz C, Jakobs C, Salomons GS.

Mol Genet Metab. 2007 May;91(1):1-6. Epub 2007 Mar 1.

PubMed [citation]
PMID:
17336114
See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000029011.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From GeneReviews, SCV000040470.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

Converted during submission to Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1not providednot providednot providednot providedAssert pathogenicitynot providednot providednot providednot provided

From Illumina Clinical Services Laboratory,Illumina, SCV000914270.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedphenotyping onlynot 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providedvalidationnot providednot providednot providednot provided

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Natera, Inc., SCV001454106.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 23, 2021

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