U.S. flag

An official website of the United States government

NM_000156.6(GAMT):c.59G>C (p.Trp20Ser) AND Cerebral creatine deficiency syndrome

Germline classification:
Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:
Jan 21, 2024
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV000799554.12

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:
Cerebral creatine deficiency syndrome (CCAD)
Synonyms:
Creatine deficiency syndromes
Identifiers:
MONDO: MONDO:0000456; MedGen: C5244016; Orphanet: 79172; OMIM: PS300352

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000939222Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jan 21, 2024) 		germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV001999934Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Nov 2, 2021) 		germlinecuration

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, curation

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

Guanidinoacetate methyltransferase deficiency identified in adults and a child with mental retardation.

Caldeira Araújo H, Smit W, Verhoeven NM, Salomons GS, Silva S, Vasconcelos R, Tomás H, Tavares de Almeida I, Jakobs C, Duran M.

Am J Med Genet A. 2005 Mar 1;133A(2):122-7.

PubMed [citation]
PMID:
15651030
See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000939222.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 20 of the GAMT protein (p.Trp20Ser). This variant is present in population databases (rs80338734, gnomAD 0.01%). This missense change has been observed in individual(s) with cerebral creatine deficiency syndrome (PMID: 15108290, 15651030, 16855203, 17336114, 21140503). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8303). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GAMT protein function. Experimental studies have shown that this missense change affects GAMT function (PMID: 17336114). For these reasons, this variant has been classified as Pathogenic.

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

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001999934.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (2)

Description

The p.Trp20Ser variant in GAMT has been reported in at least 9 individuals with cerebral creatine deficiency syndrome (PMID: 15108290, 15651030, 16855203), segregated with disease in 4 affected relatives from 3 families (PMID: 15651030, 16855203), and has been identified in 0.01% (3/27420) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs140115503). 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 9 affected individuals, 8 of those were homozygotes, which increases the likelihood that the p.Trp20Ser variant is pathogenic (PMID: 15108290, 15651030, 16855203). This variant has also been reported in ClinVar (Variation ID#: 8303) and has been interpreted as pathogenic by Illumina Clinical Services Laboratory (Illumina), Mendelics, Integrated Genetics (Laboratory Corporation of America), Invitae, GeneReviews, Natera, Inc., and OMIM. In vitro functional studies provide some evidence that the p.Trp20Ser variant may slightly impact protein function (PMID: 17336114). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. 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: 15651030, 15108290, 16855203). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive cerebral creatine deficiency syndrome. ACMG/AMP Criteria applied: PM3, PP3, PS3_supporting, PM2_supporting, PP4 (Richards 2015).

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

Last Updated: Sep 29, 2024