NM_000156.6(GAMT):c.327G>A (p.Lys109=) AND Deficiency of guanidinoacetate methyltransferase

Clinical significance:Pathogenic (Last evaluated: Jun 17, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
8 submissions [Details]
Record status:
current
Accession:
RCV000020141.10

Allele description [Variation Report for NM_000156.6(GAMT):c.327G>A (p.Lys109=)]

NM_000156.6(GAMT):c.327G>A (p.Lys109=)

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.327G>A (p.Lys109=)
Other names:
p.K109K:AAG>AAA
HGVS:
  • NC_000019.10:g.1399793C>T
  • NG_009785.1:g.6761G>A
  • NM_000156.6:c.327G>AMANE SELECT
  • NM_138924.3:c.327G>A
  • NP_000147.1:p.Lys109=
  • NP_620279.1:p.Lys109=
  • NC_000019.9:g.1399792C>T
  • NM_000156.4:c.327G>A
  • NM_000156.5:c.327G>A
Links:
dbSNP: rs80338735
NCBI 1000 Genomes Browser:
rs80338735
Molecular consequence:
  • NM_000156.6:c.327G>A - synonymous variant - [Sequence Ontology: SO:0001819]
  • NM_138924.3:c.327G>A - synonymous variant - [Sequence Ontology: SO:0001819]

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
SCV000040467GeneReviewsno assertion criteria providedpathologic
(Aug 18, 2011)
not providedcuration

SCV000410914Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Pathogenic
(Apr 27, 2017)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV000893511Fulgent Genetics,Fulgent Geneticscriteria provided, single submitter
Pathogenic
(Oct 31, 2018)
unknownclinical testing

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

SCV000919410Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Feb 1, 2018)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV001156344GenomeConnect-Association for Creatine Deficiencies, Association for Creatine Deficienciesno assertion providednot providedunknownphenotyping only

SCV001443811Cytogenetics and Genomics Lab,Cyprus Institute Of Neurology and Geneticscriteria provided, single submitter
Pathogenic
(Jun 17, 2020)
inheritedresearch

PubMed (10)
[See all records that cite these PMIDs]

SCV001454104Natera, Inc.no assertion criteria providedPathogenic
(Sep 16, 2020)
germlineclinical testing

SCV001760441Genomics England Pilot Project,Genomics Englandno assertion criteria provided
Pathogenicgermlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedinheritedyes1not providednot provided1not providedresearch
not providedunknownyesnot providednot providednot providednot providednot providedphenotyping only
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providednot providednot providednot providednot providednot providednot providednot providedcuration

Citations

PubMed

Guanidinoacetate methyltransferase deficiency: the first inborn error of creatine metabolism in man.

Stöckler S, Isbrandt D, Hanefeld F, Schmidt B, von Figura K.

Am J Hum Genet. 1996 May;58(5):914-22.

PubMed [citation]
PMID:
8651275
PMCID:
PMC1914613

GAMT deficiency: features, treatment, and outcome in an inborn error of creatine synthesis.

Mercimek-Mahmutoglu S, Stoeckler-Ipsiroglu S, Adami A, Appleton R, Araújo HC, Duran M, Ensenauer R, Fernandez-Alvarez E, Garcia P, Grolik C, Item CB, Leuzzi V, Marquardt I, Mühl A, Saelke-Kellermann RA, Salomons GS, Schulze A, Surtees R, van der Knaap MS, Vasconcelos R, Verhoeven NM, Vilarinho L, et al.

Neurology. 2006 Aug 8;67(3):480-4. Epub 2006 Jul 19.

PubMed [citation]
PMID:
16855203
See all PubMed Citations (10)

Details of each submission

From GeneReviews, SCV000040467.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

Converted during submission to Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1not providednot providednot providednot providedAssert pathogenicitynot providednot providednot providednot provided

From Illumina Clinical Services Laboratory,Illumina, SCV000410914.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

The GAMT c.327G>A (p.Lys109=) variant is reported as one of the most frequently observed pathogenic variants among patients with guanidinoacetate methyltransferase deficiency accounting for 24% of disease associated alleles (Mercimek-Mahmutoglu and Salomons 2015). Across a selection of the available literature, the p.Lys109= variant has been identified in a total of 15 individuals including four in a homozygous state and 11 in a compound heterozygous state (Stockler et al. 1996; Morris et al. 2007; Dhar et al. 2009; Comeaux et al. 2013; Mercimek-Mahmutoglu et al. 2014). Unaffected heterozygous carriers of the variant were observed in two families (Stockler et al. 1996). Control data are unavailable for this variant, which is reported at a frequency of 0.00031 in the European (non-Finnish) population of the Exome Aggregation Consortium. The variant affects the last nucleotide of the splice donor site of exon 2. Experimental analysis showed the variant results in two abnormal transcripts, one from the use of a cryptic splice site in intron 2 and one resulting from skipping of exon 2. Both abnormal transcripts were identified in one compound heterozygous individual and one homozygous individual, demonstrating the effect on splicing of the variant (Stockler et al. 1996). Based on the collective evidence, the p.Lys109= variant is classified as pathogenic for guanidinoacetate methyltransferase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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

From Fulgent Genetics,Fulgent Genetics, SCV000893511.1

#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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919410.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

Variant summary: GAMT c.327G>A (p.Lys109Lys) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5 splicing donor site. These predictions are confirmed in a publication via RT-PCR analysis (though the results were not presented for evaluation; Stockler_1996). The same publication presented data showing that the activity of GAMT is significantly reduced in two patient's liver cells compared to WT, suggesting the variant affects protein function. The variant allele was found at a frequency of 0.00019 in 197356 control chromosomes. The c.327G>A variant has been reported in the literature in numerous individuals affected with Guanidinoactetate methyltransferase deficiency, both as homozygous and compound heterozygous alleles. These data indicate that the variant is very likely to be associated with disease. Additionally, in the literature it has been referred to as one of the most common mutations associated with Guanidinoactetate methyltransferase deficiency. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, both of which classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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

From GenomeConnect-Association for Creatine Deficiencies, Association for Creatine Deficiencies, SCV001156344.1

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

Description

Variant interpreted as Pathogenic and reported on 12-08-2009 by GTR ID 1006. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect facilitates ClinVar submission from the Association for Creatine Deficiencies registry and does not attempt to reinterpret the variant.

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

From Cytogenetics and Genomics Lab,Cyprus Institute Of Neurology and Genetics, SCV001443811.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedresearch PubMed (10)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1inheritedyes1not providednot provided1not providednot providednot provided

From Natera, Inc., SCV001454104.1

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

From Genomics England Pilot Project,Genomics England, SCV001760441.1

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

Last Updated: Aug 27, 2021

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