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.505C>T (p.Arg169Ter)

CA263242

55919 (ClinVar)

Gene: GATM
Condition: AGAT deficiency
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 3573c2d0-928a-44b7-9dac-e9a0a3de33b6
Approved on: 2022-06-06
Published on: 2022-10-07

HGVS expressions

NM_001482.3:c.505C>T
NM_001482.3(GATM):c.505C>T (p.Arg169Ter)
NC_000015.10:g.45368240G>A
CM000677.2:g.45368240G>A
NC_000015.9:g.45660438G>A
CM000677.1:g.45660438G>A
NC_000015.8:g.43447730G>A
NG_011674.1:g.15543C>T
NG_011674.2:g.39078C>T
ENST00000396659.8:c.505C>T
ENST00000674905.1:c.505C>T
ENST00000675158.1:c.505C>T
ENST00000675323.1:c.505C>T
ENST00000675701.1:c.445C>T
ENST00000675974.1:n.596C>T
ENST00000676090.1:c.*1236C>T
ENST00000396659.7:c.505C>T
ENST00000558163.1:c.286C>T
ENST00000558336.5:c.505C>T
ENST00000558362.5:n.2161C>T
ENST00000558916.1:n.403C>T
NM_001482.2:c.505C>T
NM_001321015.1:c.118C>T
NM_001321015.2:c.118C>T
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Pathogenic

Met criteria codes 4
PP4 PM3_Supporting PVS1 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(GATM):c.505C>T (p.Arg169Ter) variant in GATM is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 4/9 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is reported to be homozygous in a proband and sibling, both of whom have undetectable GAA in plasma and urine, and reduced creatine peak (about 2/3 normal) on brain MRS with elevated NAA/creatine ratio (PMID 20625172, 23660394, 26490222)(PP4_Strong, PM3_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 in the East Asian population. This is lower than the ClinGen CCDS VCEP's threshold for PM2_Supporting (<0.000055) meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 55919). 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
This variant is reported to be homozygous in a proband and sibling, both of whom have undetectable GAA in plasma and urine, and reduced creatine peak (about 2/3 normal) on brain MRS with elevated NAA/creatine ratio (PMID 20625172, 23660394, 26490222)(PP4_Strong).
PM3_Supporting
A proband and sibling are homozygous for the variant, and the parents were confirmed to be heterozygous (PMID 20625172, 23660394, 26490222) 0.5 points (PM3_Supporting)
PVS1
The NM_001482.3(GATM):c.505C>T (p.Arg169Ter) variant in GATM is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 4/9 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).
PM2_Supporting
The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 in the East Asian population. This is lower than the ClinGen CCDS VCEP's threshold for PM2_Supporting (<0.000055) meeting this criterion (PM2_Supporting).
Curation History
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