Variant: NM_000156.6(GAMT):c.668dup (p.Tyr223Ter)

CA9043535

445930 (ClinVar)

Gene: GAMT

Condition: guanidinoacetate methyltransferase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: f6f8e4cb-33d9-4fa9-94fb-1a80b311d2ee

Approved on: 2022-06-06

Published on: 2022-10-07

HGVS expressions

NM_000156.6:c.668dup
NM_000156.6(GAMT):c.668dup (p.Tyr223Ter)
NC_000019.10:g.1397402dup
CM000681.2:g.1397402dup
NC_000019.9:g.1397401dup
CM000681.1:g.1397401dup
NC_000019.8:g.1348401dup
NG_008283.1:g.18519dup
NG_009785.1:g.9152dup
ENST00000252288.8:c.668dup
ENST00000640164.1:n.501dup
ENST00000640762.1:c.599dup
ENST00000252288.6:c.668dup
NM_000156.5:c.668dup

Uncertain Significance

• Met criteria codes: PM2_Supporting PVS1_Moderate

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

Evidence submitted by expert panel

Cerebral Creatine Deficiency Syndromes VCEP

The NM_000156.6:c.668dupA (p.Tyr223fs) variant in GAMT is a frameshift variant in the last exon (exon 6/6; amino acid 223/237) of GAMT, and is therefore predicted to escape nonsense mediated decay. Less than 10% of the protein is predicted to be removed (PVS1_Moderate). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in published literature in individuals with GAMT deficiency. It is noted in ClinVar (Variation ID 445930). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 1.1.0): PM2_Supporting, BP4. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).

Met criteria codes

• PM2_Supporting: The variant is absent in gnomAD v2.1.1 (PM2_Supporting).
• PVS1_Moderate: The NM_000156.6:c.668dupA (p.Tyr223fs) variant in GAMT is a frameshift variant in the last exon (exon 6/6; amino acid 223/237) of GAMT, and is therefore predicted to escape nonsense mediated decay. Less than 10% of the protein is predicted to be removed (PVS1_Moderate).