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NM_000156.6(GAMT):c.403G>A (p.Asp135Asn) AND Deficiency of guanidinoacetate methyltransferase

Germline classification:
Pathogenic (5 submissions)
Last evaluated:
Jun 8, 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:
RCV001784322.12

Allele description [Variation Report for NM_000156.6(GAMT):c.403G>A (p.Asp135Asn)]

NM_000156.6(GAMT):c.403G>A (p.Asp135Asn)

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.403G>A (p.Asp135Asn)
Other names:
NM_000156.6(GAMT):c.403G>A; p.Asp135Asn
HGVS:
  • NC_000019.10:g.1399184C>T
  • NG_009785.1:g.7370G>A
  • NM_000156.6:c.403G>AMANE SELECT
  • NM_138924.3:c.403G>A
  • NP_000147.1:p.Asp135Asn
  • NP_620279.1:p.Asp135Asn
  • NC_000019.9:g.1399183C>T
  • NM_000156.5:c.403G>A
Protein change:
D135N
Links:
dbSNP: rs774144200
NCBI 1000 Genomes Browser:
rs774144200
Molecular consequence:
  • NM_000156.6:c.403G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_138924.3:c.403G>A - 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

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV002025257Revvity Omics, Revvity
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Oct 4, 2021)
germlineclinical testing

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

SCV002779689Fulgent Genetics, Fulgent Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Apr 11, 2022)
unknownclinical testing

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

SCV004009596ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen
reviewed by expert panel

(ClinGen_CCDS_ACMG_Specifications_GAMT_v1.1)
Pathogenic
(Jun 8, 2023)
germlinecuration

Citation Link,

SCV004198574Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Feb 23, 2024)
unknownclinical testing

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

SCV004698082Institute of Human Genetics, University of Leipzig Medical Center
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Feb 5, 2024)
inheritedclinical testing

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

Summary from all submissions

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

Details of each submission

From Revvity Omics, Revvity, SCV002025257.3

#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 Fulgent Genetics, Fulgent Genetics, SCV002779689.1

#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 ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen, SCV004009596.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The NM_000156.6(GAMT):c.403G>A variant in GAMT is predicted to result in the substitution of aspartate by asparagine at amino acid 135 (p.Asp135Asn). Four probands and one affected sibling have been reported with this variant, all with clinical symptoms consistent with GAMT deficiency, evidence of elevated guanidinoacetate and low creatine in plasma and/or urine, and reduced creatine on brain MRS with guanidinoacetate peak also noted for two patients. In addition, one proband was shown to have deficient GAMT activity in fibroblasts (PMID: 19027335, 19388150, 24071436, 24268530, 24415674) (PP4_Strong). Each of these individuals is compound heterozygous for the variant and another variant in GAMT that has been classified as pathogenic or likely pathogenic by the ClinGen CCDS VCEP including c.327G>A (2 patients; PMID: 24071436, 24268530, 24415674), c.299dup13 (a.k.a. c.299_311dup) (PMID: 19388150), and c.507_521dup15 (p.Cys169_Ser173dup) (PMID: 19027335)(PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00011 (2/18390 alleles) in the East Asian population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). When the variant was expressed in GAMT-deficient fibroblasts, GAMT enzyme activity was undetectable (PMID: 24415674). The computational predictor REVEL gives a score of 0.856 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3). Another variant at the same amino acid position, c.403G>T (p.Asp135Tyr), has been classified as likely pathogenic by the ClinGen CCDS VCEP (and would be likely pathogenic even without the use of PM5, therefore avoiding circular logic) (PM5_Supporting). There is a ClinVar entry for this variant (Variation ID: 573140). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency. GAMT-specific 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, PS3_Supporting, PM2_Supporting, PM5_Supporting. (Classification approved by the ClinGen CCDS VCEP on June 8, 2023)

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

From Baylor Genetics, SCV004198574.2

#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 Institute of Human Genetics, University of Leipzig Medical Center, SCV004698082.3

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

Description

Criteria applied: PM3_VSTR, PS3_SUP, PM2_SUP, PM5_SUP, PP3

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

Last Updated: Oct 13, 2024