Variant: NM_000156.6(GAMT):c.315G>A (p.Arg105=)

CA9043740

516094 (ClinVar)

Gene: GAMT

Condition: guanidinoacetate methyltransferase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: b64f0a35-1b71-4929-a4db-031692bf3e09

Approved on: 2025-03-18

Published on: 2025-03-20

HGVS expressions

NM_000156.6:c.315G>A
NM_000156.6(GAMT):c.315G>A (p.Arg105=)
NC_000019.10:g.1399805C>T
CM000681.2:g.1399805C>T
NC_000019.9:g.1399804C>T
CM000681.1:g.1399804C>T
NC_000019.8:g.1350804C>T
NG_009785.1:g.6749G>A
ENST00000252288.8:c.315G>A
ENST00000447102.8:c.315G>A
ENST00000640762.1:c.246G>A
ENST00000252288.6:c.315G>A
ENST00000447102.7:c.315G>A
NM_000156.5:c.315G>A
NM_138924.2:c.315G>A
NM_138924.3:c.315G>A

Likely Benign

• Met criteria codes: BP7 BP4

• Not Met criteria codes: PM2 BS1

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.315G>A (p.Arg105=) 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 -0.854) (BP4, BP7). To our knowledge, this variant has not been reported in the literature among individuals with GAMT deficiency and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v4.1.0. is 0.0004959 (21/42344 alleles in the E. Asian population, which is lower than the CCDS VCEP's threshold for BS1 (>0.001) and higher than the threshold for PM2_Supporting (<0.0004) (no population codes are met).There is a ClinVar entry for this v iant (Variation ID: 516094). In summary, this variant meets the criteria to be classified as likely benign for GAMT deficiency based on the GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): BP4, BP7. (Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel on March 18, 2025)

Met criteria codes

• BP7: The NM_000156.6:c.315G>A (p.Arg105=) 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 -0.854) (BP7).
• BP4: The computational predictor SpliceAI predicts that the variant has no impact on splicing (all scores <0.1) (BP4)

Not Met criteria codes

• PM2: The highest population minor allele frequency in gnomAD v4.1.0. is 0.0004959 (21/42344 alleles in the E. Asian population, which is lower than the CCDS VCEP's threshold for BS1 (>0.001) and higher than the threshold for PM2_Supporting (<0.0004) (no population codes are met).
• BS1: The highest population minor allele frequency in gnomAD v4.1.0. is 0.0004959 (21/42344 alleles in the E. Asian population, which is lower than the CCDS VCEP's threshold for BS1 (>0.001) and higher than the threshold for PM2_Supporting (<0.0004) (no population codes are met).