Variant: NM_138924.3:c.160G>C

CA402998035

Gene: GAMT

Condition: guanidinoacetate methyltransferase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: df177d38-29ce-4a53-8bc0-8131ab4fe8da

Approved on: 2023-03-09

Published on: 2023-03-29

HGVS expressions

NM_138924.3:c.160G>C
NC_000019.10:g.1401317C>G
CM000681.2:g.1401317C>G
NC_000019.9:g.1401316C>G
CM000681.1:g.1401316C>G
NC_000019.8:g.1352316C>G
NG_009785.1:g.5237G>C
ENST00000252288.8:c.160G>C
ENST00000447102.8:c.160G>C
ENST00000640762.1:c.112+48G>C
ENST00000252288.6:c.160G>C
ENST00000447102.7:c.160G>C
NM_000156.5:c.160G>C
NM_138924.2:c.160G>C
NM_000156.6:c.160G>C

Likely Pathogenic

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

• Met criteria codes: PM3_Supporting PM2_Supporting PP4_Strong 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 GAMT Version 1.1.0

Evidence submitted by expert panel

Cerebral Creatine Deficiency Syndromes VCEP

The NM_000156.6:c.160G>C (p.Ala54Pro) variant in GAMT has been previously reported in one individual with guanidinoacetate methyltransferase deficiency (PMID: 15108290). This variant is absent from population databases (PM2_Supporting). The affected individual previously reported (PMID: 15108290) was a homozygote for the variant, and harbored it in cis with two homozygous variants classified as benign in ClinVar, c.626C>T (p.Thr209Met) (ClinVar ID: 21068) and c.459+71G>A (ClinVar ID: 21067) (PM3_Supporting). This individual showed elevated urinary GAA and, GAMT enzymatic activity <0.1 nmol/h/mg in lymphoblasts, with full GAMT gene sequencing performed (PMID: 15108290) (PP4_Strong). The p.Ala54Pro variant is a missense variant that is predicted damaging by in-silico missense predictors (REVEL score 0.894) (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for guanidinoacetate methyltransferase (GAMT) 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): PM2_Supporting, PM3_Supporting, PP3, PP4_Strong (Classification approved by the ClinGen CCDS VCEP on March 9, 2023)

Met criteria codes

• PM3_Supporting: Identified in one homozygous proband, in cis with two benign variants (c.626C>T (p.Thr209Met) (ClinVar ID: 21068) and c.459+71G>A (ClinVar ID: 21067)) (PMID: 15108290) (0.5pts).
• PM2_Supporting: Absent in population databases
• PP4_Strong: PMID: 15108290: Identified in one individual who showed elevated urinary GAA (1pt), GAMT enzymatic activity <0.1 nmol/h/mg in lymphoblasts (3pts), with full GAMT gene sequencing performed (total - 4pts, PP4_Strong)
• PP3: REVEL score 0.894, >0.75 cutoff for use of PP3