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.391+15G>T

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA9043702

544259 (ClinVar)

Gene: GAMT

Condition: guanidinoacetate methyltransferase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 254e55f1-46ed-4929-9983-b1fa1b3dda1a

Approved on: 2024-11-14

Published on: 2025-03-14

HGVS expressions

NM_000156.6:c.391+15G>T

NM_000156.6(GAMT):c.391+15G>T

NC_000019.10:g.1399509C>A

CM000681.2:g.1399509C>A

NC_000019.9:g.1399508C>A

CM000681.1:g.1399508C>A

NC_000019.8:g.1350508C>A

NG_009785.1:g.7045G>T

ENST00000252288.8:c.391+15G>T

ENST00000447102.8:c.391+15G>T

ENST00000591788.3:c.74+15G>T

ENST00000640164.1:n.224+15G>T

ENST00000640762.1:c.322+15G>T

ENST00000252288.6:c.391+15G>T

ENST00000447102.7:c.391+15G>T

ENST00000591788.2:c.76+15G>T

NM_000156.5:c.391+15G>T

NM_138924.2:c.391+15G>T

NM_138924.3:c.391+15G>T

Likely Pathogenic

PM3_Supporting PP3 PP4_Strong 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.391+15G>T variant is in intron 3 of GAMT. The computational predictor, SpliceAI, predicts the creation of a new donor splice site 2 bp upstream (score 0.98) indicating that this variants may impact splicing (PP3). This variant has been identified a homozygous individual with clinical features consistent with GAMT deficiency, "decreased" GAMT enzyme activity in fibroblasts, elevated GAA and low or low normal creatine in urine, low creatine on brain MRS (PMID: 23234264, 29506905; assumed to be the same patent in both publications) (PP4_Strong, PM3_Supporting). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00003651 (43/1177768 alleles) in the European (non-Finnish) population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (ClinVar Variation ID: 544259). In summary, this variant meets the criteria to be classified as likely pathogenic for GAMT deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): PP4_Strong, PP3, PM2_Supporting, PM3_Supporting. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on November 14, 2024)

PM3_Supporting

This variant has been identified in a homozygous individual (PMID: 23234264, PMID: 29506905; assumed to be the same patient in both publications) (PM3_Supporting)

PP3

The computational splicing predictor SpliceAI gives a score of 0.98 for donor gain, predicting that the variant disrupts the donor splice site of intron 3 of GAMT (PP3).

PP4_Strong

This variant has been identified a homozygous individual with clinical features consistent with GAMT deficiency, "decreased" GAMT enzyme activity in fibroblasts, elevated GAA and low or low normal creatine in urine, low creatine on brain MRS (PMID: 23234264, 29506905; assumed to be the same patent in both publications) (PP4_Strong).

PM2_Supporting

The highest population minor allele frequency in gnomAD v4.1.0 is 0.00003651 (43/1177768 alleles) in the European (non-Finnish) population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting).

Curation History

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