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Variant: NM_001482.3(GATM):c.484+1G>T

CA341869

21299 (ClinVar)

Gene: GATM
Condition: AGAT deficiency
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: bb81130f-06d5-4290-b2e0-da5368f79924
Approved on: 2022-06-06
Published on: 2022-10-07

HGVS expressions

NM_001482.3:c.484+1G>T
NM_001482.3(GATM):c.484+1G>T
NC_000015.10:g.45369325C>A
CM000677.2:g.45369325C>A
NC_000015.9:g.45661523C>A
CM000677.1:g.45661523C>A
NC_000015.8:g.43448815C>A
NG_011674.1:g.14458G>T
NG_011674.2:g.37993G>T
ENST00000396659.8:c.484+1G>T
ENST00000674905.1:c.484+1G>T
ENST00000675158.1:c.484+1G>T
ENST00000675323.1:c.484+1G>T
ENST00000675701.1:c.424+1G>T
ENST00000675974.1:n.575+1G>T
ENST00000676090.1:c.*1215+1G>T
ENST00000396659.7:c.484+1G>T
ENST00000558163.1:c.265+1G>T
ENST00000558336.5:c.484+1G>T
ENST00000558362.5:n.2140+1G>T
ENST00000558916.1:n.382+1G>T
NM_001482.2:c.484+1G>T
NM_001321015.1:c.97+1G>T
NM_001321015.2:c.97+1G>T

Pathogenic

Met criteria codes 4
PM3_Supporting PP4 PM2_Supporting PVS1

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.484+1G>T variant in GATM occurs within the canonical splice donor site of intron 3. It was shown by RT-PCR to cause skipping of exon 3, resulting in a frameshift, premature termination codon, and nonsense-mediated decay (PMID: 22386973) (PVS1). One individual who is homozygous for the variant has been reported with significantly decreased creatine peak on H1-MRS, nondetectable enzyme activity in cultured lymphoblasts, and low GAA in plasma and low creatine in plasma (PP4_Strong, PM3_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 (1/18394) in the East Asian population, which is lower than the ClinGen CCDS VCEP's threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The variant is noted in ClinVar (Variation ID: 21299). 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
PM3_Supporting
The c.484+1G>T variant in GATM has been previously reported in an individual (PMID: 22386973) who showed significantly decreased creatine peak on H1-MRS, nondetectable enzyme activity in cultured lymphoblasts, and low GAA in plasma and low creatine in plasma (5 points total; PP4_Strong) and was homozygous for the variant (PM3_Supporting). Both of her parents were confirmed by follow-up genetic testing to be heterozygous for the variant.
PP4
The c.484+1G>T variant in GATM has been previously reported in an individual (PMID: 22386973) who showed significantly decreased creatine peak on H1-MRS, nondetectable enzyme activity in cultured lymphoblasts, and low GAA in plasma and low creatine in plasma (5 points total; PP4_Strong) and was homozygous for the variant (PM3_Supporting). Both of her parents were confirmed by follow-up genetic testing to be heterozygous for the variant.
PM2_Supporting
The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 (1/18394) in the East Asian population, which is lower than the ClinGen CCDS VCEP's threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting).
PVS1
The variant is a canonical splice-site variant and was confirmed via RT-PCR to result in skipping of exon 3, frameshift, and a prematurely truncated mRNA subject to nonsense-mediated decay (PMID: 22386973) (PVS1).
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