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NM_000156.6(GAMT):c.491G>A (p.Gly164Asp) AND Deficiency of guanidinoacetate methyltransferase

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Jun 6, 2022
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:
RCV002305456.3

Allele description [Variation Report for NM_000156.6(GAMT):c.491G>A (p.Gly164Asp)]

NM_000156.6(GAMT):c.491G>A (p.Gly164Asp)

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.491G>A (p.Gly164Asp)
Other names:
p.G164D:GGC>GAC; NM_000156.6(GAMT):c.491G>A
HGVS:
  • NC_000019.10:g.1398995C>T
  • NG_009785.1:g.7559G>A
  • NM_000156.6:c.491G>AMANE SELECT
  • NM_138924.3:c.491G>A
  • NP_000147.1:p.Gly164Asp
  • NP_620279.1:p.Gly164Asp
  • NC_000019.9:g.1398994C>T
  • NM_000156.4:c.491G>A
  • NM_000156.5:c.491G>A
  • Q14353:p.Gly164Asp
Protein change:
G164D
Links:
UniProtKB: Q14353#VAR_071785; dbSNP: rs760101382
NCBI 1000 Genomes Browser:
rs760101382
Molecular consequence:
  • NM_000156.6:c.491G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_138924.3:c.491G>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

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002600146ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen
reviewed by expert panel

(ClinGen_CCDS_ACMG_Specifications_GAMT_v1.1)		Uncertain significance
(Jun 6, 2022) 		germlinecuration

Citation Link,

SCV004198576Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Sep 25, 2023) 		unknownclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

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 ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen, SCV002600146.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The NM_000156.6:c.491G>A variant in GAMT is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 164 (p.Gly164Asp). There has been one reported case in literature with this variant; this patient had elevated plasma guanidinoacetate levels on two occasions and is compound heterozygous for the variant and a pathogenic variant in GAMT, c.522G>A (p.Trp174Ter), confirmed in trans by parental testing (PP4, PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 (1/34562 alleles) in the Latino 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 0.919 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: 203539). 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): PM3, PP4, PP3, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).

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

From Baylor Genetics, SCV004198576.1

#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