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_138924.3:c.352G>T

CA402995747

Gene: GAMT (HGNC:2593)

Condition: guanidinoacetate methyltransferase deficiency (MONDO:0012999)

Inheritance Mode: Autosomal recessive inheritance

UUID: 0623de7d-471c-4bd6-a5cc-eeaf02d16d35

Approved on: 2025-12-10

Published on: 2025-12-10

HGVS expressions

NM_138924.3:c.352G>T

NC_000019.10:g.1399563C>A

CM000681.2:g.1399563C>A

NC_000019.9:g.1399562C>A

CM000681.1:g.1399562C>A

NC_000019.8:g.1350562C>A

NG_009785.1:g.6991G>T

ENST00000252288.8:c.352G>T

ENST00000447102.8:c.352G>T

ENST00000591788.3:c.35G>T

ENST00000640164.1:n.185G>T

ENST00000640762.1:c.283G>T

ENST00000252288.6:c.352G>T

ENST00000447102.7:c.352G>T

ENST00000591788.2:c.37G>T

NM_000156.5:c.352G>T

NM_138924.2:c.352G>T

NM_000156.6:c.352G>T

Pathogenic

PVS1 PP4_Moderate PM2_Supporting

PM3

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.352G>T (p.Glu118*) variant in GAMT is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 3/6, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been detected in at least one individual with GAMT deficiency (PMID: 40105081), who was compound heterozygous for this variant and a likely pathogenic variant c.327+43G>A, which was confirmed in trans by parental testing. This patient had significantly decreased creatine peak on brain MRS (GAA not reported) (PP4_Moderate). This variant is absent in gnomAD v4.1.0. (PM2_Supporting). There is no ClinVar entry for this variant. In summary, this variant meets the criteria to be classified as 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, PM2_Supporting, PP4_Moderate. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on December 10, 2025)

PVS1

The NM_000156.6:c.352G>T variant in GAMT is a nonsense variant variant predicted to cause a premature stop codon in biologically-relevant-exon 3/6, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).

PP4_Moderate

PMID: 40105081: 1 individual with this variant had significantly reduced creatine peak on brain MRS (GAA not reported) (3pts) (PP4_Moderate); no biochemical data reported

PM2_Supporting

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

PM3

1 case, compound het for c.352G>T (p.Glu118*) (paternally inherited) and c.327+43G>A (maternally inherited) (PMID: 40105081). This occurrence was not used for PM3 evidence here as it was used as PM3 evidence for the c.327+43G>A variant, thereby preventing circularity.

Curation History

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