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Variant: NM_001482.3(GATM):c.565C>T (p.Arg189Cys)

CA7542898

225915 (ClinVar)

Gene: GATM
Condition: AGAT deficiency
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 3922b100-047f-4637-b91f-394c286c2cba
Approved on: 2023-01-24
Published on: 2023-01-25

HGVS expressions

NM_001482.3:c.565C>T
NM_001482.3(GATM):c.565C>T (p.Arg189Cys)
NC_000015.10:g.45368180G>A
CM000677.2:g.45368180G>A
NC_000015.9:g.45660378G>A
CM000677.1:g.45660378G>A
NC_000015.8:g.43447670G>A
NG_011674.1:g.15603C>T
NG_011674.2:g.39138C>T
ENST00000396659.8:c.565C>T
ENST00000674905.1:c.565C>T
ENST00000675158.1:c.565C>T
ENST00000675323.1:c.565C>T
ENST00000675701.1:c.505C>T
ENST00000675974.1:n.656C>T
ENST00000676090.1:c.*1296C>T
ENST00000396659.7:c.565C>T
ENST00000558163.1:c.346C>T
ENST00000558336.5:c.565C>T
ENST00000558362.5:n.2221C>T
ENST00000558916.1:n.463C>T
NM_001482.2:c.565C>T
NM_001321015.1:c.178C>T
NM_001321015.2:c.178C>T

Uncertain Significance

Met criteria codes 2
PS3_Supporting PP3
Not Met criteria codes 2
BS1 PM2

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 1.1.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Cerebral Creatine Deficiency Syndromes VCEP
The NM_001482.3:c.565C>T variant in GATM is a missense variant that is predicted to result in the substitution of arginine by cysteine at amino acid 189 (p.Arg189Cys). To our knowledge, this variant has not been reported in individuals with AGAT deficiency in the published literature. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 (1/16246 alleles) in the African population (none of the population data codes are met). When overexpressed in HeLa cells, the variant resulted in <10% of wild-type enzyme activity (PMID: 27233232) (PS3_Supporting). There is a ClinVar entry for this variant (Variation ID: 225915). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for AGAT deficiency. GATM-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PS3_Supporting, PP3. (Classification approved by the ClinGen CCDS VCEP on January 24, 2023).
Met criteria codes
PS3_Supporting
When overexpressed in HeLa cells, the variant resulted in <10% of wild-type enzyme activity (PMID: 27233232).
PP3
REVEL score 0.881 (>0.75 cutoff for PP3)
Not Met criteria codes
BS1
The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 (1/16246 alleles) in the African population (none of the population data codes are met).
PM2
The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 (1/16246 alleles) in the African population (none of the population data codes are met).
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