Evidence Repository - Clinical Genome Resources

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

Link to SEPIO compliant JSON-LD document

Variant: NM_001482.3(GATM):c.669T>C (p.Tyr223=)

CA291037

137449 (ClinVar)

Gene: GATM

Condition: AGAT deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 4c740182-a1b2-4f99-9c4d-054cdd843778

Approved on: 2023-01-25

Published on: 2023-01-25

HGVS expressions

NM_001482.3:c.669T>C

NM_001482.3(GATM):c.669T>C (p.Tyr223=)

NC_000015.10:g.45368076A>G

CM000677.2:g.45368076A>G

NC_000015.9:g.45660274A>G

CM000677.1:g.45660274A>G

NC_000015.8:g.43447566A>G

NG_011674.1:g.15707T>C

NG_011674.2:g.39242T>C

ENST00000396659.8:c.669T>C

ENST00000674905.1:c.669T>C

ENST00000675158.1:c.669T>C

ENST00000675323.1:c.669T>C

ENST00000675701.1:c.609T>C

ENST00000675974.1:n.760T>C

ENST00000676090.1:c.*1400T>C

ENST00000396659.7:c.669T>C

ENST00000558163.1:c.450T>C

ENST00000558336.5:c.669T>C

ENST00000558362.5:n.2325T>C

ENST00000558916.1:n.567T>C

NM_001482.2:c.669T>C

NM_001321015.1:c.282T>C

NM_001321015.2:c.282T>C

Benign

BP4 BP7 BA1

PP3 PM2

Evidence Links 0

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 1.1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Cerebral Creatine Deficiency Syndromes VCEP

The NM_001482.3:c.669T>C (p.Tyr223=) variant in GATM is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by PhyloP (BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00501 (125/24958 alleles) in the African population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.0005), and therefore meets this criterion (BA1). The computational splicing predictor SpliceAI gives a score of 0.0 for donor and acceptor loss suggesting that the variant has no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 137449). In summary, this variant meets the criteria to be classified as benign 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 1.1.0): BA1, BP4, BP7. (Classification approved by the ClinGen CCDS VCEP on January 25, 2023).

BP4

No predicted effect on splicing (Splice AI <0.2, varSEAK class 1)

BP7

Nucleotide is not highly conserved and no predicted effect on splicing (Splice AI <0.2, varSEAK class 1)

BA1

gnomAD: 0.501% in African population

PP3

No predicted effect on splicing (Splice AI <0.2, varSEAK class 1)

PM2

gnomAD: 0.501% in African population

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