Variant: NM_000156.6(GAMT):c.134G>A (p.Trp45Ter)

CA402998096

2419155 (ClinVar)

Gene: GAMT

Condition: guanidinoacetate methyltransferase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 683bc758-d93c-4fd6-a8f9-f9c5cd7a5bfa

Approved on: 2023-10-12

Published on: 2023-11-08

HGVS expressions

NM_000156.6:c.134G>A
NM_000156.6(GAMT):c.134G>A (p.Trp45Ter)
NC_000019.10:g.1401343C>T
CM000681.2:g.1401343C>T
NC_000019.9:g.1401342C>T
CM000681.1:g.1401342C>T
NC_000019.8:g.1352342C>T
NG_009785.1:g.5211G>A
ENST00000252288.8:c.134G>A
ENST00000447102.8:c.134G>A
ENST00000640762.1:c.112+22G>A
ENST00000252288.6:c.134G>A
ENST00000447102.7:c.134G>A
NM_000156.5:c.134G>A
NM_138924.2:c.134G>A
NM_138924.3:c.134G>A

Pathogenic

• Met criteria codes: PM2_Supporting PP4 PM3 PVS1

• Not Met criteria codes: BS1 BA1

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

Evidence submitted by expert panel

Cerebral Creatine Deficiency Syndromes VCEP

The NM_000156.6:c.134G>A (p.Trp45Ter) variant in GAMT is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 1/6 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 two probands with GAMT deficiency. Of those probands, both were homozygous for the variant (PMIDs 31222513, 33996490) (PM3). At least one proband (two siblings) with this variant had elevated GAA and low creatine in plasma (PP4). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 2419155). In summary, this variant meets the criteria to be classified as pathogenic for GAMT 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, PM3, PP4, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on Oct 12, 2023)

Met criteria codes

• PM2_Supporting: Absent from gnomAD
• PP4: Variant found homozygous in two affected siblings with elevated plasma GAA and low creatine levels.
• PM3: Variant observed in the homozygous state in two probands with clinical features of GAMT deficiency
• PVS1: Nonsense variant in exon 1

Not Met criteria codes

• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline