Variant: NM_138924.3:c.220G>C

CA402997017

Gene: GAMT

Condition: guanidinoacetate methyltransferase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 9262800f-6b30-4ede-af2c-601847eaadf7

Approved on: 2023-03-23

Published on: 2023-03-29

HGVS expressions

NM_138924.3:c.220G>C
NC_000019.10:g.1399900C>G
CM000681.2:g.1399900C>G
NC_000019.9:g.1399899C>G
CM000681.1:g.1399899C>G
NC_000019.8:g.1350899C>G
NG_009785.1:g.6654G>C
ENST00000252288.8:c.220G>C
ENST00000447102.8:c.220G>C
ENST00000640762.1:c.151G>C
ENST00000252288.6:c.220G>C
ENST00000447102.7:c.220G>C
NM_000156.5:c.220G>C
NM_138924.2:c.220G>C
NM_000156.6:c.220G>C

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

• Met criteria codes: PP4_Moderate PS3_Supporting PP3 PM3 PM2_Supporting

• Not Met criteria codes: PM5

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 GAMT Version 1.1.0

Evidence submitted by expert panel

Cerebral Creatine Deficiency Syndromes VCEP

The NM_000156.6:c.220G>C (p.Ala74Pro) variant in GAMT has been previously reported in two unrelated individuals with guanidinoacetate methyltransferase deficiency (PMID: 24415674). This variant is absent from population databases (PM2_Supporting). Of the two unrelated affected individuals previously reported (PMID: 24415674), one was a homozygote and the other was a reported compound heterozygote who carried a reported pathogenic variant (c.327G>A, see ClinVar Variation ID: 21065) with unknown phase (PM3). The homozygous individual who was previously reported showed an absent creatine peak on brain magnetic resonance spectroscopy (MRS) (PP4_Moderate). The p.Ala74Pro variant is a missense variant that is predicted damaging by in-silico missense predictors (REVEL score 0.93) (PP3). This variant was shown to result in undetectable GAMT enzymatic activity when transfected into GAMT-deficient fibroblasts (PMID: 24415674) (PS3_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for guanidinoacetate methyltransferase deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel (CCDS VCEP) (Specifications version 1.1.0): PS3_Supporting, PM2_Supporting, PM3, PP3, PP4_Moderate (Richards 2015). (Classification approved by the ClinGen CCDS VCEP on March 23, 2023)

Met criteria codes

• PP4_Moderate: Identified in one proband who showed absent creatine peak and GAA peak on MRS (3pts) (PMID: 24415674)
• PS3_Supporting: The p.Ala74Pro variant was shown to result in undetectable GAMT enzyme activity in GAMT-deficient fibroblasts (PMID: 24415674)
• PP3: REVEL score 0.93, >0.75 cutoff for use of PP3
• PM3: Identified in two unrelated individuals with guanidinoacetate methyltransferase deficiency (PMID: 24415674): one was a homozygote for the variant (0.5pts) and the other was a reported compound heterozygote who carried a reported pathogenic variant (c.327G>A, see ClinVar Variation ID: 21065) with unknown phase (0.5pts) (1pt total)
• PM2_Supporting: Absent in population databases.

Not Met criteria codes

• PM5: A different missense variant at the same amino acid residue, p.Ala74Thr has been reported as a VUS in ClinVar (Variation ID:651193)