Variant: NM_000156.6(GAMT):c.145del (p.Tyr49fs)

CA631301060

695019 (ClinVar)

Gene: GAMT

Condition: guanidinoacetate methyltransferase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 7aa4c0b5-0a11-4732-8122-cb6094f65f10

Approved on: 2023-09-14

Published on: 2023-11-08

HGVS expressions

NM_000156.6:c.145del
NM_000156.6(GAMT):c.145del (p.Tyr49fs)
NC_000019.10:g.1401332del
CM000681.2:g.1401332del
NC_000019.9:g.1401331del
CM000681.1:g.1401331del
NC_000019.8:g.1352331del
NG_009785.1:g.5222del
ENST00000252288.8:c.145del
ENST00000447102.8:c.145del
ENST00000640762.1:c.112+33del
ENST00000252288.6:c.145del
ENST00000447102.7:c.145del
NM_000156.5:c.145del
NM_138924.2:c.145del
NM_138924.3:c.145del

Pathogenic

• Met criteria codes: PP4 PM3_Supporting PVS1 PM2_Supporting

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.145del (p.Tyr49Ilefs*65) variant in GAMT is a frameshift variant that is predicted to cause a premature stop codon in biologically-relevant-exon 3/6, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). A Spanish patient, who is homozygous for the variant, has been reported with clinical symptoms consistent with GAMT deficiency, elevated guanidinoacetate in urine and plasma, and deficient GAMT activity in fibroblasts (PMID: 19892372, 21140503) (PP4_Strong, PM3_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0000373 (1/26808 alleles) in the Lation/Admixed American 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 (Variation ID: 695019). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (CCDS VCEP) (Specifications Version 1.1.0): PVS1, PP4_Strong, PM2_Supporting, PM3_Supporting. (Classification approved by the ClinGen CCDS VCEP on Sept. 14, 2023)

Met criteria codes

• PP4: A Spanish patient has been reported with clinical symptoms consistent with GAMT deficiency, elevated guanidinoacetate in urine and plasma, and deficient GAMT activity in fibroblasts (PMID: 19892372, 21140503) (PP4_Strong).
• PM3_Supporting: One patient has been reported who is homozygous for the variant (PMID: 19892372, 21140503).
• PVS1: The NM_000156.6:c.145del (p.Tyr49Ilefs*65) variant in GAMT is a frameshift variant that is predicted to cause a premature stop codon in biologically-relevant-exon 3/6, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).
• PM2_Supporting: The highest population minor allele frequency in gnomAD v2.1.1 is 0.0000373 (1/26808 alleles) in the Lation/Admixed American population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting).