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_001482.3(GATM):c.1111dup (p.Met371fs)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA344713

55918 (ClinVar)

Gene: GATM

Condition: AGAT deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 1ad7be29-ad14-4f7a-9207-e9e7ac4cc6d9

Approved on: 2022-06-06

Published on: 2022-10-07

HGVS expressions

NM_001482.3:c.1111dup

NM_001482.3(GATM):c.1111dup (p.Met371fs)

NC_000015.10:g.45363948dup

CM000677.2:g.45363948dup

NC_000015.9:g.45656146dup

CM000677.1:g.45656146dup

NC_000015.8:g.43443438dup

NG_011674.1:g.19835dup

NG_011674.2:g.43370dup

ENST00000396659.8:c.1111dup

ENST00000674905.1:c.1111dup

ENST00000675158.1:c.*11dup

ENST00000675323.1:c.1111dup

ENST00000675701.1:c.1051dup

ENST00000675974.1:n.1982dup

ENST00000676090.1:c.*1842dup

ENST00000396659.7:c.1111dup

ENST00000558336.5:c.1111dup

ENST00000558362.5:n.2767dup

NM_001482.2:c.1111dup

NM_001321015.1:c.724dup

NM_001321015.2:c.724dup

Pathogenic

PP4_Strong PM2_Supporting PM3_Supporting PVS1_Strong

BA1 BS1

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 GATM Version 1

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Cerebral Creatine Deficiency Syndromes VCEP

The NM_001482.3:c.1111dup (p.Met371AsnfsTer6) variant in GATM is a frameshift variant predicted to cause a premature stop codon in the last 50 nucleotides of the penultimate exon 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 two siblings with AGAT deficiency who had significantly decreased creatine peak on brain MRS (PMID 20682460) (PP4_Strong). Both individuals were homozygous for the variant, confirmed in trans by parental testing (PMID 20682460) (PM3_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PVS1_Strong, PP4_Strong, PM3_Supporting, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).

PP4_Strong

Two siblings, both homozygous for the variant, have clinical and biochemical features consistent with AGAT deficiency including undetectable creatine on brain MRS (3 pts), and low guanidinoacetate in urine (1 pt) (PMID 20682460) (PP4_Strong).

PM2_Supporting

Absent from gnomAD v2.1.1 (PM2_Supporting).

PM3_Supporting

Variant identified in homozygous state in proband and sibling; parental testing confirmed in trans (0.5 point).

PVS1_Strong

Frameshift variant leading to premature stop within the last 50 bp of penultimate exon that removes >10% of protein.

BA1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Curation History

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