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]

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Variant: NM_000156.6(GAMT):c.64dup (p.Ala22fs)

CA631301051

1402763 (ClinVar)

Gene: GAMT

Condition: guanidinoacetate methyltransferase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 9eb5a533-ebbe-4fc3-82b4-92fffdb9847c

HGVS expressions

NM_000156.6:c.64dup

NM_000156.6(GAMT):c.64dup (p.Ala22fs)

NC_000019.10:g.1401418dup

CM000681.2:g.1401418dup

NC_000019.9:g.1401417dup

CM000681.1:g.1401417dup

NC_000019.8:g.1352417dup

NG_009785.1:g.5141dup

ENST00000252288.8:c.64dup

ENST00000447102.8:c.64dup

ENST00000640762.1:c.64dup

ENST00000252288.6:c.64dup

ENST00000447102.7:c.64dup

NM_000156.5:c.64dup

NM_138924.2:c.64dup

NM_138924.3:c.64dup

Pathogenic

PVS1 PM3 PM2_Supporting PP4_Strong

Evidence Links 0

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.64dup (p.Ala22GlyfsTer63) variant in GAMT is a frameshift variant predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Two affected unrelated individuals, previously reported (PMID: 27650626, PMID: 15108290), were homozygous for the variant; one of these individuals (PMID: 15108290) had elevated urinary guanidinoacetate and absent GAMT enzyme activity in fibroblasts with full GAMT gene sequencing performed, and the other proband (PMID: 27650626) had low serum and urine creatinine and absent creatine peak on brain MRS. (PM3, PP4_Strong), This variant is absent from population databases (PM2_Supporting). This variant has also been reported in ClinVar (Variation ID: 1402763). In summary, this variant meets criteria to be classified as pathogenic for guanidinoacetate methyltransferase deficiency. GAMT-specific ACMG/AMP criteria applied (Specifications Version 1.1.0): PVS1, PP4_Strong, PM2_Supporting, PM3, PP4_Strong. (Classification approved by the ClinGen CCDS VCEP on March 9, 2023)

PVS1

This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 22 and leads to a premature termination codon 63 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the GAMT gene is an established disease mechanism in guanidinoacetate methyltransferase deficiency.

PM3

Identified in two affected individuals, both of whom were homozygous for the variant (PMID: 27650626, PMID: 15108290) (1pt).

PM2_Supporting

Absent in gnomAD

PP4_Strong

Identified in one proband (PMID: 15108290) with elevated urinary GAA and absent GAMT enzyme activity in fibroblasts with full GAMT gene sequencing performed (4pts; PP4_Strong); also identified in another proband (PMID: 27650626) with low serum and urine creatinine and absent creatine peak on brain MRS (3pts; PP4_Moderate).

Approved on: 2023-03-09

Published on: 2023-03-29

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