Variant: NM_000156.6(GAMT):c.578A>G (p.Gln193Arg)

CA402991040

1328978 (ClinVar)

Gene: GAMT

Condition: guanidinoacetate methyltransferase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 3f02c0ad-66d2-4a7a-ba73-caad164e4a8b

HGVS expressions

NM_000156.6:c.578A>G
NM_000156.6(GAMT):c.578A>G (p.Gln193Arg)
NC_000019.10:g.1397492T>C
CM000681.2:g.1397492T>C
NC_000019.9:g.1397491T>C
CM000681.1:g.1397491T>C
NC_000019.8:g.1348491T>C
NG_008283.1:g.18609T>C
NG_009785.1:g.9062A>G
ENST00000252288.8:c.578A>G
ENST00000640164.1:n.411A>G
ENST00000640762.1:c.509A>G
ENST00000252288.6:c.578A>G
NM_000156.5:c.578A>G

Uncertain Significance

• Met criteria codes: PM2_Supporting PP4_Strong

• Not Met criteria codes: PP3 PM3 BP4

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.578A>G (p.Gln193Arg) variant in GAMT has been identified in one individual with guanidinoacetate methyltransferase deficiency (PMID: 23846910). This variant is absent from the Genome Aggregation Database (gnomAD, https://gnomad.broadinstitute.org/) and was identified in 0.021% (2/9,546) chromosomes with no homozygotes in the 4.7KJPN database (PM2_Supporting). This variant has also been reported in ClinVar (Variation ID: 1328978) and was interpreted as a variant of uncertain significance by LabCorp Women's Health and Genetics/Laboratory Corporation of America. The patient previously reported was a reported compound heterozygote that carried a likely pathogenic variant (c.391G>C (p.Gly131Arg; CA402995480; PS3_Supporting, PM2_Supporting, PP3, PP4_Strong). This individual showed absent creatine peak on brain magnetic resonance spectroscopy and elevated urine GAA with low creatine with full GAMT gene sequencing (PP4_Strong). The p.Gln193Arg variant is a missense variant whose impact is uncertain based on in silico missense predictors (REVEL score 0.626). In summary, the clinical significance of the p.Gln193Arg variant is uncertain. 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): PM2_Supporting, PP4_Strong (Richards 2015). (Classification approved by the ClinGen CCDS VCEP on March 23, 2023)

Met criteria codes

• PM2_Supporting: Absent in gnomAD; identified in 2/9,546 chromosomes with 0 homozygotes in the 4.7KJPN database.
• PP4_Strong: PMID: 23846910: Patient showed absent creatine peak on brain magnetic resonance spectroscopy (3pts) and elevated urine GAA with low creatine (1pt) with full GAMT gene sequencing (PP4_Strong, 4pts total)

Not Met criteria codes

• PP3: REVEL score 0.626, <0.75 cutoff for use of PP3
• PM3: PMID: 23846910: Identified in one patient who was a reported compound heterozygote that carried a likely pathogenic variant (c.391G>C (p.Gly131Arg; CA402995480; PS3_Supporting, PM2_Supporting, PP3, PP4_Strong) (0.25pts)
• BP4: REVEL score 0.626, <0.5 cutoff for use of BP4

Approved on: 2023-03-23

Published on: 2023-03-29