Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_001482.3(GATM):c.446G>A (p.Trp149Ter)

CA340668

7302 (ClinVar)

Gene: GATM
Condition: AGAT deficiency
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 1a58ace5-4d7e-455d-9355-602d96764ba2
Approved on: 2022-06-06
Published on: 2022-10-07

HGVS expressions

NM_001482.3:c.446G>A
NM_001482.3(GATM):c.446G>A (p.Trp149Ter)
NC_000015.10:g.45369364C>T
CM000677.2:g.45369364C>T
NC_000015.9:g.45661562C>T
CM000677.1:g.45661562C>T
NC_000015.8:g.43448854C>T
NG_011674.1:g.14419G>A
NG_011674.2:g.37954G>A
ENST00000396659.8:c.446G>A
ENST00000674905.1:c.446G>A
ENST00000675158.1:c.446G>A
ENST00000675323.1:c.446G>A
ENST00000675701.1:c.386G>A
ENST00000675974.1:n.537G>A
ENST00000676090.1:c.*1177G>A
ENST00000396659.7:c.446G>A
ENST00000558163.1:c.227G>A
ENST00000558336.5:c.446G>A
ENST00000558362.5:n.2102G>A
ENST00000558537.5:c.59G>A
ENST00000558916.1:n.344G>A
ENST00000561148.5:c.59G>A
NM_001482.2:c.446G>A
NM_001321015.1:c.59G>A
NM_001321015.2:c.59G>A
More

Pathogenic

Met criteria codes 4
PP4_Strong PVS1 PM3_Supporting PM2_Supporting

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Cerebral Creatine Deficiency Syndromes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GATM Version 1

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Cerebral Creatine Deficiency Syndromes VCEP
The NM_001482.3:c.446G>A (p.Trp149Ter) variant in GATM is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 3/9 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Three siblings and a cousin with AGAT deficiency are all homozygous for the variant (PM3_Supporting). The proband in this family has total absence of the creatine/phosphocreatine peak on brain MRS, low urine GAA and creatine but normal blood levels; AGAT activity in lymphoblasts <0.3 nmol/hr/mg protein (normal 12.6–23.4)(PP4_Strong). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 7302). In summary, this variant meets the criteria to be classified as pathogenic for AGAT deficiency. GATM-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 1.1.0): PVS1, PP4_Strong, PM3_Supporting, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).
Met criteria codes
PP4_Strong
The proband in a family of 4 affected individuals has total absence of the creatine/phosphocreatine peak on brain MRS, low urine GAA and creatine but normal blood levels; AGAT activity in lymphoblasts <0.3 nmol/hr/mg protein (normal 12.6–23.4)(PP4_Strong).
PVS1
The NM_001482.3:c.446G>A (p.Trp149Ter) variant in GATM is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 3/9 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).
PM3_Supporting
Three affected siblings and an affected cousin are all homozygous for the variant. 0.5 points (PM3_Supporting).
PM2_Supporting
This variant is absent in gnomAD v2.1.1 (PM2_Supporting).
Curation History
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.