Variant: NM_000156.6(GAMT):c.228A>T (p.Ser76=)

CA9043761

1552732 (ClinVar)

Gene: GAMT

Condition: guanidinoacetate methyltransferase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: c0b25d34-300f-4066-a90f-4e5bf4bf85c0

Approved on: 2024-10-08

Published on: 2024-10-25

HGVS expressions

NM_000156.6:c.228A>T
NM_000156.6(GAMT):c.228A>T (p.Ser76=)
NC_000019.10:g.1399892T>A
CM000681.2:g.1399892T>A
NC_000019.9:g.1399891T>A
CM000681.1:g.1399891T>A
NC_000019.8:g.1350891T>A
NG_009785.1:g.6662A>T
ENST00000252288.8:c.228A>T
ENST00000447102.8:c.228A>T
ENST00000640762.1:c.159A>T
ENST00000252288.6:c.228A>T
ENST00000447102.7:c.228A>T
NM_000156.5:c.228A>T
NM_138924.2:c.228A>T
NM_138924.3:c.228A>T

Uncertain Significance

• Met criteria codes: BP4 BP7 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 2.0.0

Evidence submitted by expert panel

Cerebral Creatine Deficiency Syndromes VCEP

The NM_000156.6:c.228A>T (p.Ser76=) variant in GAMT is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by phyloP (score -0.250) (BP4, BP7). To our knowledge, this variant has not been reported among individuals with GAMT deficiency and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v4.1.0. is 0.0001008 (6/59514 alleles) in the 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: 1552732). In summary, this variant meets the criteria to be classified as a variant of uncertain significance 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 2.0.0): PM2_Supporting, BP4, BP7. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on October 8th, 2024).

Met criteria codes

• BP4: Not predicted by SpliceAI to impact splicing (alll scores <0.1) (BP4)
• BP7: The NM_000156.6:c.228A>T (p.Ser76=) variant in GAMT is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by phyloP (score -0.250) (BP7).
• PM2_Supporting: The highest population minor allele frequency in gnomAD v4.1.0. is 0.0001008 (6/59514 alleles) in the Admixed American population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting).