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NM_000156.6(GAMT):c.476T>C (p.Leu159Pro) AND Deficiency of guanidinoacetate methyltransferase

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Mar 23, 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:
RCV003159214.2

Allele description [Variation Report for NM_000156.6(GAMT):c.476T>C (p.Leu159Pro)]

NM_000156.6(GAMT):c.476T>C (p.Leu159Pro)

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.476T>C (p.Leu159Pro)
Other names:
NM_000156.6(GAMT):c.476T>C; p.Leu159Pro
HGVS:
  • NC_000019.10:g.1399010A>G
  • NG_009785.1:g.7544T>C
  • NM_000156.6:c.476T>CMANE SELECT
  • NM_138924.3:c.476T>C
  • NP_000147.1:p.Leu159Pro
  • NP_620279.1:p.Leu159Pro
  • NC_000019.9:g.1399009A>G
Protein change:
L159P
Links:
dbSNP: rs2144636453
NCBI 1000 Genomes Browser:
rs2144636453
Molecular consequence:
  • NM_000156.6:c.476T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_138924.3:c.476T>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

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003852718ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen
reviewed by expert panel

(ClinGen_CCDS_ACMG_Specifications_GAMT_v1.1)		Likely pathogenic
(Mar 23, 2023) 		germlinecuration

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

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Citations

PubMed

Thirteen new patients with guanidinoacetate methyltransferase deficiency and functional characterization of nineteen novel missense variants in the GAMT gene.

Mercimek-Mahmutoglu S, Ndika J, Kanhai W, de Villemeur TB, Cheillan D, Christensen E, Dorison N, Hannig V, Hendriks Y, Hofstede FC, Lion-Francois L, Lund AM, Mundy H, Pitelet G, Raspall-Chaure M, Scott-Schwoerer JA, Szakszon K, Valayannopoulos V, Williams M, Salomons GS.

Hum Mutat. 2014 Apr;35(4):462-9. doi: 10.1002/humu.22511. Epub 2014 Mar 6.

PubMed [citation]
PMID:
24415674

Details of each submission

From ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen, SCV003852718.1

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

Description

The NM_000156.6:c.476T>C (p.Leu159Pro) variant in GAMT has been identified in one individual with guanidinoacetate methyltransferase deficiency (PMID: 24415674). This variant is absent in population databases (PM2_Supporting). The patient previously reported was a homozygote for the variant (PMID: 24415674) (PM3_Supporting). This individual showed an absent creatine peak and an absent GAA peak on brain MRS (PP4_Moderate). The p.Leu159Pro variant is a missense variant that is predicted damaging by in-silico missense predictors (REVEL score 0.947) (PP3). This variant was shown to result in undetectable GAMT enzyme activity in GAMT-deficient fibroblasts (PMID: 24415674) (PS3_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for guanidinoacetate methyltransferase (GAMT) deficiency. GAMT-specific ACMG/AMP Criteria applied, as specified by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel (CCDS VCEP) (Specifications version 1.1.0): PS3_Supporting, PM2_Supporting, PM3_Supporting, PP3, PP4_Moderate (Richards 2015). (Classification approved by the ClinGen CCDS VCEP on March 23, 2023)

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

Last Updated: Oct 8, 2024