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.148A>C (p.Met50Leu)

CA254380

8305 (ClinVar)

Gene: GAMT

Condition: guanidinoacetate methyltransferase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 562504e1-86d3-4fa5-818a-0eecd910d7b4

HGVS expressions

NM_000156.6:c.148A>C

NM_000156.6(GAMT):c.148A>C (p.Met50Leu)

NC_000019.10:g.1401329T>G

CM000681.2:g.1401329T>G

NC_000019.9:g.1401328T>G

CM000681.1:g.1401328T>G

NC_000019.8:g.1352328T>G

NG_009785.1:g.5225A>C

ENST00000252288.8:c.148A>C

ENST00000447102.8:c.148A>C

ENST00000640762.1:c.112+36A>C

ENST00000252288.6:c.148A>C

ENST00000447102.7:c.148A>C

NM_000156.5:c.148A>C

NM_138924.2:c.148A>C

NM_138924.3:c.148A>C

Likely Pathogenic

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

PM3_Supporting PM2_Supporting PS3_Supporting PP4_Strong PP3

PM5

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.148A>C (p.Met50Leu) variant in GAMT has been previously reported in one individual with guanidinoacetate methyltransferase deficiency (PMID: 17101918). This variant is absent from population databases (PM2_Supporting). The affected individual previously reported (PMID: 17101918) was a homozygote for the variant and had a low creatine peak on brain MRS, elevated urinary GAA, low creatine/creatinine ratio, with DNA sequence analysis of GAMT (PM3_Supporting, PP4_Strong). The p.Met50Leu variant is a missense variant that is predicted damaging by in-silico missense predictors (REVEL score 0.923) (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 (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_Strong (Classification approved by the ClinGen CCDS VCEP on March 9, 2023)

PM3_Supporting

PMID: 17101918: Reported in the homozygous state in one patient with guanidinoacetate methyltransferase deficiency (0.5pts)

PM2_Supporting

Absent in population databases.

PS3_Supporting

The p.Met50Leu variant was shown to result in undetectable GAMT enzymatic activity when transfected into GAMT-deficient fibroblasts (PMID: 24415674)

The p.Met50Leu variant was shown to result in undetectable GAMT enzymatic activity when transfected into GAMT-deficient fibroblasts PubMed:24415674

PP4_Strong

PMID: 17101918: Found in proband with low creatine peak on brain MRS (3pts), elevated urinary GAA (1pts), low creatine/creatinine ratio, with DNA sequence analysis of GAMT (PP4_Strong)

PP3

REVEL score 0.923, >0.75 cutoff for use of PP3

PM5

A different missense variant at the same amino acid residue, p.Met50Ile, has been previously reported and interpreted as a VUS in ClinVar (Variation ID: 566179)

Approved on: 2023-03-09

Published on: 2023-03-29

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