Variant: NM_001482.3(GATM):c.1209del (p.Gly404fs)

CA891843836

570204 (ClinVar)

Gene: GATM

Condition: AGAT deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 655a67d6-8fab-4250-9925-ba532dd557c6

Approved on: 2025-04-11

Published on: 2025-04-11

HGVS expressions

NM_001482.3:c.1209del
NM_001482.3(GATM):c.1209del (p.Gly404fs)
NC_000015.10:g.45362172del
CM000677.2:g.45362172del
NC_000015.9:g.45654370del
CM000677.1:g.45654370del
NC_000015.8:g.43441662del
NG_011674.1:g.21611del
NG_011674.2:g.45146del
ENST00000396659.8:c.1209del
ENST00000674905.1:c.*171del
ENST00000675158.1:c.*109del
ENST00000675323.1:c.*1711del
ENST00000675701.1:c.1149del
ENST00000675974.1:n.3758del
ENST00000676090.1:c.*1940del
ENST00000396659.7:c.1209del
ENST00000558362.5:n.2865del
NM_001482.2:c.1209del
NM_001321015.1:c.822del
NM_001321015.2:c.822del

Uncertain Significance

• Met criteria codes: PVS1_Strong PM2_Supporting

• Not Met criteria codes: BA1 BS1

Expert Panel

Cerebral Creatine Deficiency Syndromes VCEP

Criteria Specification Information

Criteria Specification: ClinGen Cerebral Creatine Deficiency Syndromes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GATM Version 2.0.0

Evidence submitted by expert panel

Cerebral Creatine Deficiency Syndromes VCEP

The NM_001482.3:c.1209del (p.Gly404AlafsTer24) variant in GATM is a frameshift variant predicted to cause a premature stop codon in the last exon of the gene and therefore to escape nonsense mediated decay. Less than 10% of the protein is predicted to be removed; however, the truncated/altered region includes the active site residue Cys407 that is critical to protein function (PVS1_Strong; PMIDs 9148748, 9218780, 9266688). To our knowledge, this variant has not been reported in the literature in an individual with features of AGAT deficiency. This variant is absent in gnomAD v4.1.0. (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 570204). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PVS1_Strong, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on April 11, 2025).

Met criteria codes

• PVS1_Strong: The NM_001482.3:c.1209del (p.Gly404AlafsTer24) variant in GATM is a frameshift variant predicted to cause a premature stop codon in the last exon of the gene and therefore to escape nonsense mediated decay. Less than 10% of the protein is predicted to be removed; however, the truncated/altered region includes the active site residue Cys407 that is critical to protein function (PVS1_Strong; PMIDs 9148748, 9218780, 9266688).
• PM2_Supporting: Variant absent from gnomAD v4.1.0. (PM2_Supporting).

Not Met criteria codes

• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline