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NM_000156.6(GAMT):c.407C>T (p.Thr136Met) AND Deficiency of guanidinoacetate methyltransferase

Germline classification:
Pathogenic (6 submissions)
Last evaluated:
Oct 26, 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:
RCV001253217.8

Allele description [Variation Report for NM_000156.6(GAMT):c.407C>T (p.Thr136Met)]

NM_000156.6(GAMT):c.407C>T (p.Thr136Met)

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.407C>T (p.Thr136Met)
Other names:
NM_000156.6(GAMT):c.407C>T; p.Thr136Met
HGVS:
  • NC_000019.10:g.1399180G>A
  • NG_009785.1:g.7374C>T
  • NM_000156.6:c.407C>TMANE SELECT
  • NM_138924.3:c.407C>T
  • NP_000147.1:p.Thr136Met
  • NP_620279.1:p.Thr136Met
  • NC_000019.9:g.1399179G>A
  • NM_000156.4:c.407C>T
  • NM_000156.5:c.407C>T
Protein change:
T136M
Links:
dbSNP: rs374724533
NCBI 1000 Genomes Browser:
rs374724533
Molecular consequence:
  • NM_000156.6:c.407C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_138924.3:c.407C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

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
SCV001428825Institute of Human Genetics, University of Leipzig Medical Center
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Jan 7, 2019)
germlineclinical testing

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

SCV001454102Natera, Inc.
no assertion criteria provided
Likely pathogenic
(Sep 16, 2020)
germlineclinical testing

SCV002047666GenomeConnect-Association for Creatine Deficiencies, Association for Creatine Deficiencies
no classification provided
not providedmaternalphenotyping only

SCV002783482Fulgent Genetics, Fulgent Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Nov 6, 2021)
unknownclinical testing

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

SCV004198582Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Mar 11, 2024)
unknownclinical testing

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

SCV004227927ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen
reviewed by expert panel

(ClinGen_CCDS_ACMG_Specifications_GAMT_v1.1)
Pathogenic
(Oct 26, 2023)
germlinecuration

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, curation
not providedmaternalyesnot providednot providednot providednot providednot providedphenotyping only
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

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

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 Institute of Human Genetics, University of Leipzig Medical Center, SCV001428825.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

This variant was identified as homozygous

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

From Natera, Inc., SCV001454102.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From GenomeConnect-Association for Creatine Deficiencies, Association for Creatine Deficiencies, SCV002047666.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedphenotyping onlynot provided

Description

Variant interpreted as Likely pathogenic and reported on 04-18-2018 by lab or GTR ID MedGenome. GenomeConnect - Association for Creatine Deficiencies assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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

From Fulgent Genetics, Fulgent Genetics, SCV002783482.1

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

From Baylor Genetics, SCV004198582.2

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

From ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen, SCV004227927.1

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

Description

The NM_000156.6:c.407C>T variant in GAMT is a missense variant predicted to cause substitution of threonine by methionine at amino acid 136 (p.Thr136Met). This variant has been detected in 3 unrelated individuals with GAMT deficiency (PMID: 24415674, PMID: 21140503, ClinVar SCV001428825.1). Of those individuals, two were compound heterozygous for the variant and a pathogenic variant, c.316C>T (p.Q106*) in unknown phase (PMID: 24415674, PMID: 21140503) and 1 was homozygous for the variant (ClinVar SCV001428825.1) (1.5pts total, PM3). One of these individuals had elevated GAA in plasma, deficient GAMT enzyme activity (<5% wild-type enzyme) in fibroblasts, and significantly reduced creatine peak on brain MRS (PMID: 21140503) and one individual had an absent creatine peak with visible GAA peak on brain MRS (PMID: 24415674) (PP4_Strong). Expression of the variant in GAMT-deficient fibroblasts resulted in <5% wild type GAMT activity indicating that this variant may impact protein function (PMID: 24415674)(PS3_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000009 (1/113420 alleles) in the European (non-Finnish) population, which is lower 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 0.976 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3_Moderate). There is a ClinVar entry for this variant (Variation ID: 544257). 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): PP4_Strong, PM3, PP3_Moderate, PS3_Supporting, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on Oct. 2026, 2023)

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

Last Updated: Sep 29, 2024