Variant: NM_000156.6(GAMT):c.521G>A (p.Trp174Ter)

CA9043619

801414 (ClinVar)

Gene: GAMT

Condition: guanidinoacetate methyltransferase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 39dddb09-bbe9-4b3a-a619-cd83b0bea7cd

Approved on: 2025-03-18

Published on: 2025-03-20

HGVS expressions

NM_000156.6:c.521G>A
NM_000156.6(GAMT):c.521G>A (p.Trp174Ter)
NC_000019.10:g.1398965C>T
CM000681.2:g.1398965C>T
NC_000019.9:g.1398964C>T
CM000681.1:g.1398964C>T
NC_000019.8:g.1349964C>T
NG_009785.1:g.7589G>A
ENST00000252288.8:c.521G>A
ENST00000447102.8:c.521G>A
ENST00000591788.3:c.204G>A
ENST00000640164.1:n.354G>A
ENST00000640762.1:c.452G>A
ENST00000252288.6:c.521G>A
ENST00000447102.7:c.521G>A
ENST00000591788.2:c.206G>A
NM_000156.5:c.521G>A
NM_138924.2:c.521G>A
NM_138924.3:c.521G>A

Pathogenic

• Met criteria codes: PM2_Supporting PP4_Strong PVS1_Strong PM3

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 2.0.0

Evidence submitted by expert panel

Cerebral Creatine Deficiency Syndromes VCEP

The NM_000156.6:c.521G>A (p.Trp174Ter) variant in GAMT is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 5 out of a total of 6 exons. The variant occurs at the border of the last 50 nucleotides of the penultimate exon of GAMT. As a result, nonsense-mediated decay may not occur. In that case, >10% of the protein is predicted to be lost (PVS1_Strong). The variant has been identified in a female Spanish patient with clinical features consistent with GAMT deficiency, elevated urine guanidinoacetate, and very low GAMT activity in fibroblasts (PMID: 15108290, 16855203, 21140503) (PP4_Strong). This patient is compound heterozygous for the variant and another variant in GAMT that has been classified as pathogenic by the ClinGen CCDS VCEP, c.59G>C (p.Trp20Ser) (ClinVar Variation ID: 8303; SCV004009593.1). The variants were confirmed to be in trans by parental DNA sequencing. 1 point (PM3). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00002196 (2/91090 alleles; no homozygotes) in the South Asian population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). Another variant resulting in p.Trp174Ter (c.522G>A) (ClinVar Variation ID: 205584) has been reported and has been classified as pathogenic by the ClinGen CCDS VCEP. There is a ClinVar entry for the variant (Variation ID 801414). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency. ACMG/AMP GANT-specific criteria applied, as specified by the ClinGen CCDS VCEP (Version 2.0.0): PVS1_Strong, PM3, PP4_Strong, PM2_Supporting. (Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel on March 18, 2025)

Met criteria codes

• PM2_Supporting: The highest population minor allele frequency in gnomAD v4.1.0. is 0.00002196 (2/91090 alleles; no homozygotes) in the South Asian population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting).
• PP4_Strong: The variant has been identified in a female Spanish patient with clinical features consistent with GAMT deficiency, elevated urine guanidinoacetate, and very low GAMT activity in fibroblasts (PMID: 15108290, 16855203, 21140503) (PP4_Strong).
• PVS1_Strong: The NM_000156.6:c.521G>A (p.Trp174Ter) variant in GAMT is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 5 out of a total of 6 exons. The variant occurs at the border of the last 50 nucleotides of the penultimate exon of GAMT. As a result, nonsense-mediated decay may not occur. In that case, >10% of the protein is predicted to be lost (PVS1_Strong).
• PM3: One patient is compound heterozygous for the variant and another variant in GAMT that has been classified as pathogenic by the ClinGen CCDS VCEP, c.59G>C (p.Trp20Ser) (ClinVar Variation ID: 8303; SCV004009593.1). The variants were confirmed to be in trans by parental DNA sequencing. 1 point (PM3).