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NM_000156.6(GAMT):c.522G>C (p.Trp174Cys) AND Deficiency of guanidinoacetate methyltransferase

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Dec 12, 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:
RCV003482169.2

Allele description [Variation Report for NM_000156.6(GAMT):c.522G>C (p.Trp174Cys)]

NM_000156.6(GAMT):c.522G>C (p.Trp174Cys)

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.522G>C (p.Trp174Cys)
Other names:
NM_138924.3:c.522G>C
HGVS:
  • NC_000019.10:g.1398964C>G
  • NG_009785.1:g.7590G>C
  • NM_000156.6:c.522G>CMANE SELECT
  • NM_138924.3:c.522G>C
  • NP_000147.1:p.Trp174Cys
  • NP_620279.1:p.Trp174Cys
  • NC_000019.9:g.1398963C>G
Protein change:
W174C
Molecular consequence:
  • NM_000156.6:c.522G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_138924.3:c.522G>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

Recent activity

Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004227933ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen
reviewed by expert panel

(ClinGen_CCDS_ACMG_Specifications_GAMT_v1.1)		Uncertain significance
(Dec 12, 2023) 		germlinecuration

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Details of each submission

From ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen, SCV004227933.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The NM_000156.6:c.522G>C variant in GAMT is a missense variant predicted to cause substitution of a tryptophan by cysteine at amino acid 174 (p.Trp174Cys). To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v4.0. is 0.00002227 (1/44900 alleles) in the East Asian population, which lower is than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.813 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: 2421360. In summary, this variant meets the criteria to be classified as a variant of uncertain significance 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): PP3, PM2_Supporting. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on December 12, 2023).

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

Last Updated: Sep 29, 2024