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]

Variant: NM_000156.6(GAMT):c.577C>T (p.Gln193Ter)

CA402991043

2503890 (ClinVar)

Gene: GAMT (HGNC:2593)

Condition: guanidinoacetate methyltransferase deficiency (MONDO:0012999)

Inheritance Mode: Autosomal recessive inheritance

UUID: 69dfad77-097d-47bc-aeb9-67c5f7cf4773

Approved on: 2025-12-10

Published on: 2025-12-10

HGVS expressions

NM_000156.6:c.577C>T

NM_000156.6(GAMT):c.577C>T (p.Gln193Ter)

NC_000019.10:g.1397493G>A

CM000681.2:g.1397493G>A

NC_000019.9:g.1397492G>A

CM000681.1:g.1397492G>A

NC_000019.8:g.1348492G>A

NG_008283.1:g.18610G>A

NG_009785.1:g.9061C>T

ENST00000252288.8:c.577C>T

ENST00000640164.1:n.410C>T

ENST00000640762.1:c.508C>T

ENST00000252288.6:c.577C>T

NM_000156.5:c.577C>T

Likely Pathogenic

PVS1_Strong PP4 PM3 PM2_Supporting

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 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Cerebral Creatine Deficiency Syndromes VCEP

The NM_000156.6:c.577C>T (Gln193Ter) variant in GAMT is a nonsense variant predicted to cause a premature stop codon in the last exon of the gene and therefore to escape nonsense mediated decay. More than 10% of the protein is predicted to be removed (PVS1_Strong). This variant has been detected in at least 2 individuals with GAMT deficiency (PMID: 23234264, 31130284), who were both homozygous for the variant (PM3). One of these patients had elevated urine GAA with low creatine (PMID: 23234264) (PP4). This variant is absent in gnomAD v4.1.0. (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 2503890). In summary, this variant meets the criteria to be classified as likely pathogenic for GAMT deficiency based on the GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PVS1_Strong, PM2_Supporting, PM3, PP4. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on December 10, 2025)

PVS1_Strong

The NM_000156.6:c.577C>T (Gln193*) variant in GAMT is a nonsense variant predicted to cause a premature stop codon in the last exon of the gene and therefore to escape nonsense mediated decay. More than than 10% of the protein is predicted to be removed (PVS1_Strong).

PP4

One of these patients had elevated urine GAA with low creatine (PMID: 23234264) (PP4).

PM3

This variant has been detected in at least 2 individuals with GAMT deficiency (PMID: 23234264, 31130284), who were both homozygous for the variant (1pt total) (PM3).

PM2_Supporting

This variant is absent in gnomAD v4.1.0. (PM2_Supporting).

Curation History

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