VCV002446453.2 - ClinVar

NM_000156.6(GAMT):c.274A>G (p.Asn92Asp)

Germline

Top reviewed classifications are shown here.

Submission summary:

2 submissions

2 submitters

1 condition

Reviewed by expert panel

Uncertain significance

Jan 2023 by ClinGen Cerebr… FDA Recognized Database

for Deficiency of guanidinoacetate methyltransferase

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000156.6(GAMT):c.274A>G (p.Asn92Asp)

Variation ID: 2446453 Accession: VCV002446453.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.3 19: 1399846 (GRCh38) [ NCBI UCSC ] 19: 1399845 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 9, 2023	Dec 30, 2023	Jan 12, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000156.6:c.274A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000147.1:p.Asn92Asp	missense
NM_138924.3:c.274A>G	NP_620279.1:p.Asn92Asp	missense
NC_000019.10:g.1399846T>C
NC_000019.9:g.1399845T>C
NG_009785.1:g.6708A>G

... more HGVS ... less HGVS

Protein change

N92D

Other names

NM_138924.3:c.274A>G

Canonical SPDI

NC_000019.10:1399845:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
GAMT		-	-	GRCh38 GRCh37	467	663

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Deficiency of guanidinoacetate methyltransferase	Uncertain significance (2)	reviewed by expert panel	Jan 12, 2023	RCV003159287.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Jan 12, 2023)	reviewed by expert panel (ClinGen_CCDS_ACMG_Specifications_GAMT_v1.1) Method: curation	Deficiency of guanidinoacetate methyltransferase (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen FDA Recognized Database Accession: SCV003852703.1 First in ClinVar: Apr 09, 2023 Last updated: Apr 09, 2023	Publications: PubMed (1) PubMed: 24415674 Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/a430849d-26c4-42f2-a413-c79e51cad973 Comment: The NM_000156.6:c.274A>G variant in GAMT is a missense variant that is predicted to result in the substitution of asparagine by aspartate at amino acid 92 … (more) The NM_000156.6:c.274A>G variant in GAMT is a missense variant that is predicted to result in the substitution of asparagine by aspartate at amino acid 92 (p.Asn92Asp). This variant has been previously reported in one individual with elevated urine guanidinoacetate and low urine creatine who was homozygous for the variant (PMID: 19288536) (PP4, PM3_Supporting). This variant is absent from population databases (PM2_Supporting). The variant is predicted damaging by in-silico missense predictors (REVEL score 0.92) (PP3). This variant was shown to result in undetectable GAMT enzymatic activity when transfected into GAMT-deficient fibroblasts (PMID: 24415674) (PS3_Supporting). In summary, the clinical significance of the p.Asn92Asp variant is currently uncertain but tending towards likely pathogenic. GAMT-specific ACMG/AMP criteria applied: PS3_Supporting, PM2_Supporting, PM3_Supporting, PP3, PP4. (Classification approved by the ClinGen CCDS VCEP on January 12, 2023). (less)
Likely pathogenic (Apr 24, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Deficiency of guanidinoacetate methyltransferase Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004198595.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023

Comment:

The NM_000156.6:c.274A>G variant in GAMT is a missense variant that is predicted to result in the substitution of asparagine by aspartate at amino acid 92 (p.Asn92Asp). This variant has been previously reported in one individual with elevated urine guanidinoacetate and low urine creatine who was homozygous for the variant (PMID: 19288536) (PP4, PM3_Supporting). This variant is absent from population databases (PM2_Supporting). The variant is predicted damaging by in-silico missense predictors (REVEL score 0.92) (PP3). This variant was shown to result in undetectable GAMT enzymatic activity when transfected into GAMT-deficient fibroblasts (PMID: 24415674) (PS3_Supporting). In summary, the clinical significance of the p.Asn92Asp variant is currently uncertain but tending towards likely pathogenic. GAMT-specific ACMG/AMP criteria applied: PS3_Supporting, PM2_Supporting, PM3_Supporting, PP3, PP4. (Classification approved by the ClinGen CCDS VCEP on January 12, 2023).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Thirteen new patients with guanidinoacetate methyltransferase deficiency and functional characterization of nineteen novel missense variants in the GAMT gene.	Mercimek-Mahmutoglu S	Human mutation	2014	PMID: 24415674
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/a430849d-26c4-42f2-a413-c79e51cad973	-	-	-	-

Text-mined citations for this variant ...

Record last updated Dec 30, 2023

ClinVar Genomic variation as it relates to human health

NM_000156.6(GAMT):c.274A>G (p.Asn92Asp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...