NM_000156.6(GAMT):c.668dup (p.Tyr223Ter) 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:: RCV001272267.2

Allele description [Variation Report for NM_000156.6(GAMT):c.668dup (p.Tyr223Ter)]

NM_000156.6(GAMT):c.668dup (p.Tyr223Ter)

Gene:

GAMT:guanidinoacetate N-methyltransferase [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

19p13.3

Genomic location:

Preferred name:

NM_000156.6(GAMT):c.668dup (p.Tyr223Ter)

Other names:

NM_000156.6(GAMT):c.668dup; p.Tyr223Ter

HGVS:

NC_000019.10:g.1397402dup
NG_008283.1:g.18519dup
NG_009785.1:g.9152dup
NM_000156.6:c.668dupMANE SELECT
NP_000147.1:p.Tyr223Ter
NC_000019.9:g.1397400_1397401insT
NC_000019.9:g.1397401dup
NM_000156.6:c.668dupAMANE SELECT

Protein change:

Y223*

Links:

dbSNP: rs781163821

NCBI 1000 Genomes Browser:

rs781163821

Molecular consequence:

NM_000156.6:c.668dup - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Deficiency of guanidinoacetate methyltransferase (CCDS2)
Synonyms:: CEREBRAL CREATINE DEFICIENCY SYNDROME 2
Identifiers:: MONDO: MONDO:0012999; MedGen: C0574080; Orphanet: 382; OMIM: 612736

Recent activity

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Homo sapiens folliculin interacting protein 1 (FNIP1), transcript variant 2, mRN...
Homo sapiens folliculin interacting protein 1 (FNIP1), transcript variant 2, mRNA
gi|1676318663|ref|NM_001008738.3|

Nucleotide
RecName: Full=Guanine nucleotide-binding protein G(i) subunit alpha-3; AltName: ...
RecName: Full=Guanine nucleotide-binding protein G(i) subunit alpha-3; AltName: Full=G(i) alpha-3
gi|27805469|sp|Q9DC51.3|GNAI3_MOUSE

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001454094	Natera, Inc.	no assertion criteria provided	Uncertain significance (Sep 16, 2020)	germline	clinical testing
SCV002600165	ClinGen 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)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001454094

Natera, Inc.

no assertion criteria provided

Uncertain significance
(Sep 16, 2020)

germline

clinical testing

SCV002600165

ClinGen 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)

germline

curation

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Details of each submission

From Natera, Inc., SCV001454094.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen, SCV002600165.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The NM_000156.6:c.668dupA (p.Tyr223fs) variant in GAMT is a frameshift variant in the last exon (exon 6/6; amino acid 223/237) of GAMT, and is therefore predicted to escape nonsense mediated decay. Less than 10% of the protein is predicted to be removed (PVS1_Moderate). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in published literature in individuals with GAMT deficiency. It is noted in ClinVar (Variation ID 445930). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 1.1.0): PM2_Supporting, BP4. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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