Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_000156.6(GAMT):c.476T>C (p.Leu159Pro)

CA402994686

1335317 (ClinVar)

Gene: GAMT

Condition: guanidinoacetate methyltransferase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 7ed0a7a6-a85c-4faf-8a42-5ac1a5559d6b

Approved on: 2023-03-23

Published on: 2023-03-29

HGVS expressions

NM_000156.6:c.476T>C

NM_000156.6(GAMT):c.476T>C (p.Leu159Pro)

NC_000019.10:g.1399010A>G

CM000681.2:g.1399010A>G

NC_000019.9:g.1399009A>G

CM000681.1:g.1399009A>G

NC_000019.8:g.1350009A>G

NG_009785.1:g.7544T>C

ENST00000252288.8:c.476T>C

ENST00000447102.8:c.476T>C

ENST00000591788.3:n.159T>C

ENST00000640164.1:n.309T>C

ENST00000640762.1:c.407T>C

ENST00000252288.6:c.476T>C

ENST00000447102.7:c.476T>C

ENST00000591788.2:n.161T>C

NM_000156.5:c.476T>C

NM_138924.2:c.476T>C

NM_138924.3:c.476T>C

Likely Pathogenic

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

PM2_Supporting PP3 PP4_Moderate PM3_Supporting PS3_Supporting

Evidence Links 1

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Cerebral Creatine Deficiency Syndromes VCEP

The NM_000156.6:c.476T>C (p.Leu159Pro) variant in GAMT has been identified in one individual with guanidinoacetate methyltransferase deficiency (PMID: 24415674). This variant is absent in population databases (PM2_Supporting). The patient previously reported was a homozygote for the variant (PMID: 24415674) (PM3_Supporting). This individual showed an absent creatine peak and an absent GAA peak on brain MRS (PP4_Moderate). The p.Leu159Pro variant is a missense variant that is predicted damaging by in-silico missense predictors (REVEL score 0.947) (PP3). This variant was shown to result in undetectable GAMT enzyme activity in GAMT-deficient fibroblasts (PMID: 24415674) (PS3_Supporting). In summary, this variant meets 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): PS3_Supporting, PM2_Supporting, PM3_Supporting, PP3, PP4_Moderate (Richards 2015). (Classification approved by the ClinGen CCDS VCEP on March 23, 2023)

PM2_Supporting

Absent from population databases

PP3

REVEL score 0.947, >0.75 cutoff for use of PP3

PP4_Moderate

PMID: 24415674: Identified in one homozygous proband, who showed an absent creatine peak and absent GAA peak on brain MRS (3pts)

PM3_Supporting

PMID: 24415674: Identified in one homozygous proband (0.5pts)

PS3_Supporting

PMID: 24415674: Variant shown to result in undetectable GAMT enzymatic activity when expressed in GAMT-deficient fibroblasts

PMID: 24415674: Variant shown to result in undetectable GAMT enzymatic activity when expressed in GAMT-deficient fibroblasts PubMed:24415674

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