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NM_000156.6(GAMT):c.402C>G (p.Tyr134Ter) AND Deficiency of guanidinoacetate methyltransferase

Germline classification:
Pathogenic (3 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:
RCV001780138.6

Allele description [Variation Report for NM_000156.6(GAMT):c.402C>G (p.Tyr134Ter)]

NM_000156.6(GAMT):c.402C>G (p.Tyr134Ter)

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.402C>G (p.Tyr134Ter)
Other names:
NM_000156.6(GAMT):c.402C>G; p.Tyr134Ter
HGVS:
  • NC_000019.10:g.1399185G>C
  • NG_009785.1:g.7369C>G
  • NM_000156.6:c.402C>GMANE SELECT
  • NM_138924.3:c.402C>G
  • NP_000147.1:p.Tyr134Ter
  • NP_620279.1:p.Tyr134Ter
  • NC_000019.9:g.1399184G>C
  • NM_000156.5:c.402C>G
Protein change:
Y134*
Links:
dbSNP: rs556829801
NCBI 1000 Genomes Browser:
rs556829801
Molecular consequence:
  • NM_000156.6:c.402C>G - nonsense - [Sequence Ontology: SO:0001587]
  • NM_138924.3:c.402C>G - nonsense - [Sequence Ontology: SO:0001587]

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
SCV002024177Revvity Omics, Revvity
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Jun 10, 2021)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004009594ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen
reviewed by expert panel

(ClinGen_CCDS_ACMG_Specifications_GAMT_v1.1)
Pathogenic
(May 25, 2023)
germlinecuration

Citation Link,

SCV005058881Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Dec 23, 2023)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Revvity Omics, Revvity, SCV002024177.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen, SCV004009594.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The NM_000156.6:c.402C>G (p.Tyr134Ter) variant in GAMT is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 4/6 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 in the South Asian population, which is lower than the ClinGen CCDS VCEP's threshold for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has been detected in one individual with GAMT deficiency (PMID: 19027335). This individual had elevated GAA and low creatine in plasma and significantly decreased creatine peak and visible GAA peak on brain MRS with full GAMT gene sequencing (PMID: 19027335) (PP4_Strong). There is a ClinVar entry for this variant (Variation ID: 947458, 2 star review status) with 3 submitters classifying the variant as 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): PVS1, PM2_Supporting, PP4_Strong. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 25, 2023)

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

From Baylor Genetics, SCV005058881.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024