NM_000156.6(GAMT):c.521G>A (p.Trp174Ter) AND Cerebral creatine deficiency syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Aug 16, 2023
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:: RCV001386710.10

Allele description [Variation Report for NM_000156.6(GAMT):c.521G>A (p.Trp174Ter)]

NM_000156.6(GAMT):c.521G>A (p.Trp174Ter)

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.521G>A (p.Trp174Ter)

Other names:

NM_000156.6(GAMT):c.521G>A; p.Trp174Ter

HGVS:

NC_000019.10:g.1398965C>T
NG_009785.1:g.7589G>A
NM_000156.6:c.521G>AMANE SELECT
NM_138924.3:c.521G>A
NP_000147.1:p.Trp174Ter
NP_620279.1:p.Trp174Ter
NC_000019.9:g.1398964C>T
NM_000156.5:c.521G>A

Protein change:

W174*

Links:

dbSNP: rs200444143

NCBI 1000 Genomes Browser:

rs200444143

Molecular consequence:

NM_000156.6:c.521G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_138924.3:c.521G>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

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

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Nudt7 nudix hydrolase 7 [Mus musculus]
Nudt7 nudix hydrolase 7 [Mus musculus]
Gene ID:67528

Gene
67528[uid] AND (alive[prop]) (1)
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001587054	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 16, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 15108290, 28492532
SCV001999908	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 2, 2021)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 21140503, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001587054

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 16, 2023)

germline

clinical testing

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

SCV001999908

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Nov 2, 2021)

germline

curation

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001587054.4

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

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 801414). This premature translational stop signal has been observed in individual(s) with guanidinoacetate methyltransferase deficiency (PMID: 15108290). This variant is present in population databases (rs200444143, gnomAD 0.003%). 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).

#	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 Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001999908.2

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

Description

The p.Trp174Ter (c.521G>A) variant in GAMT has been reported in 2 individuals with cerebral creatine deficiency syndrome (PMID: 15108290, 19892372) and has been identified in in 0.003% (1/30614) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs200444143). 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 2 affected individuals, 1 was a compound heterozygote that carried a reported likely pathogenic variant in trans, and 1 was a compound heterozygote that carried a reported likely pathogenic variant with unknown phase, which increases the likelihood that the p.Trp174Ter variant is pathogenic (VariationID: 8303; PMID: 15108290, 19892372). This variant has also been reported in ClinVar (Variation ID#: 801414) and has been interpreted as pathogenic by Invitae and Mendelics. In vitro functional studies provide some evidence that the p.Trp174Ter variant may impact protein function (PMID: 21140503). However, these types of assays may not accurately represent biological function. 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 compound heterozygous for this variant is highly specific for cerebral creatine deficiency syndrome based on strict biochemical investigations consistent with disease (PMID: 15108290, 19892372). 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, PS3_supporting (Richards 2015).

#	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

Last Updated: Sep 29, 2024

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