Variant: NM_001482.3(GATM):c.407C>T (p.Thr136Met)

CA314868

205613 (ClinVar)

Gene: N/A

Condition: AGAT deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 8ecdc806-d5b5-4a80-98a9-ce7424f5b9aa

Approved on: 2023-01-25

Published on: 2023-01-25

HGVS expressions

NM_001482.3(GATM):c.407C>T (p.Thr136Met)
NC_000015.10:g.45369403G>A
CM000677.2:g.45369403G>A
NC_000015.9:g.45661601G>A
CM000677.1:g.45661601G>A
NC_000015.8:g.43448893G>A
NG_011674.1:g.14380C>T
NG_011674.2:g.37915C>T
ENST00000396659.8:c.407C>T
ENST00000674905.1:c.407C>T
ENST00000675158.1:c.407C>T
ENST00000675323.1:c.407C>T
ENST00000675701.1:c.347C>T
ENST00000675974.1:n.498C>T
ENST00000676090.1:c.*1138C>T
ENST00000396659.7:c.407C>T
ENST00000558118.1:c.*212C>T
ENST00000558163.1:c.188C>T
ENST00000558336.5:c.407C>T
ENST00000558362.5:n.2063C>T
ENST00000558537.5:c.20C>T
ENST00000558916.1:n.305C>T
ENST00000559885.1:c.20C>T
ENST00000561148.5:c.20C>T
NM_001482.2:c.407C>T
NM_001321015.1:c.20C>T
NM_001482.3:c.407C>T
NM_001321015.2:c.20C>T

Benign

• Met criteria codes: BS3_Supporting BP4 BA1

• Not Met criteria codes: PM2 PS3 PP3

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

Evidence submitted by expert panel

Cerebral Creatine Deficiency Syndromes VCEP

The NM_001482.3:c.407C>T variant in GATM is a missense variant predicted to cause substitution of threonine by methionine at amino acid 136 (p.Thr136Met). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0007357 (95/129130 alleles) in the non-Finnish European population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.0005), and therefore meets this criterion (BA1). Expression of the variant in HeLa cells resulted in >50% wild type AGAT activity suggesting that this variant does not significantly impact protein function (PMID: 27233232) (BS3_Supporting). The computational predictor REVEL gives a score of 0.049 which is below the threshold of 0.15, evidence that does not predict a damaging effect on AGAT function (BP4). There is a ClinVar entry for this variant (Variation ID: 205613). 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 1.0): BA1, BS3_Supporting, BP4. (Classification approved by the ClinGen CCDS VCEP on January 25, 2023).

Met criteria codes

• BS3_Supporting: >30% normal AGAT activity when expressed in HeLa cells.
• BP4: REVEL = 0.049
• BA1: 0.074% in non-Finnish European population in gnomAD

Not Met criteria codes

• PM2: 0.074% in non-Finnish European population in gnomAD
• PS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline