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.432G>A (p.Trp144Ter)

CA402995151

1391239 (ClinVar)

Gene: GAMT (HGNC:2593)

Condition: guanidinoacetate methyltransferase deficiency (MONDO:0012999)

Inheritance Mode: Autosomal recessive inheritance

UUID: 81f58b0c-e8be-4b55-80d9-c3b4231e7873

Approved on: 2024-04-26

Published on: 2024-07-02

HGVS expressions

NM_000156.6:c.432G>A

NM_000156.6(GAMT):c.432G>A (p.Trp144Ter)

NC_000019.10:g.1399155C>T

CM000681.2:g.1399155C>T

NC_000019.9:g.1399154C>T

CM000681.1:g.1399154C>T

NC_000019.8:g.1350154C>T

NG_009785.1:g.7399G>A

ENST00000252288.8:c.432G>A

ENST00000447102.8:c.432G>A

ENST00000591788.3:c.115G>A

ENST00000640164.1:n.265G>A

ENST00000640762.1:c.363G>A

ENST00000252288.6:c.432G>A

ENST00000447102.7:c.432G>A

ENST00000591788.2:c.117G>A

NM_000156.5:c.432G>A

NM_138924.2:c.432G>A

NM_138924.3:c.432G>A

Pathogenic

PM3_Supporting PP4_Moderate PM2_Supporting PVS1

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.432G>A variant in GAMT is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 4 out of 6, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been previously reported in one individual with GAMT deficiency (PMID: 36911476). This individual was homozygous for the variant (PM3_Supporting). This individual had significantly decreased creatine peak on brain MRS (PP4_Moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 1391239). 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 1.1.0): PVS1, PM2_Supporting, PM3_Supporting, PP4_Moderate. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on April 26, 2024)

PM3_Supporting

This variant has been previously reported in one individual with GAMT deficiency (PMID: 36911476). This individual was homozygous for the variant (PM3_Supporting).

PP4_Moderate

This individual had significantly decreased creatine peak on brain MRS (PP4_Moderate)

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

PVS1

Curation History

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