Variant: NM_000156.6(GAMT):c.225G>A (p.Ala75=)

CA291013

137433 (ClinVar)

Gene: GAMT

Condition: guanidinoacetate methyltransferase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 6c5ec147-018b-46b8-93a3-24a7fdde31b5

Approved on: 2023-03-09

Published on: 2023-03-29

HGVS expressions

NM_000156.6:c.225G>A
NM_000156.6(GAMT):c.225G>A (p.Ala75=)
NC_000019.10:g.1399895C>T
CM000681.2:g.1399895C>T
NC_000019.9:g.1399894C>T
CM000681.1:g.1399894C>T
NC_000019.8:g.1350894C>T
NG_009785.1:g.6659G>A
ENST00000252288.8:c.225G>A
ENST00000447102.8:c.225G>A
ENST00000640762.1:c.156G>A
ENST00000252288.6:c.225G>A
ENST00000447102.7:c.225G>A
NM_000156.5:c.225G>A
NM_138924.2:c.225G>A
NM_138924.3:c.225G>A

Likely Benign

• Met criteria codes: BP4 BS1

• Not Met criteria codes: BP7

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(GAMT):c.225G>A (p.Ala75=) variant is a synonymous variant for which splicing prediction algorithms (SpliceAI, varSEAK) predict no impact to the splice consensus sequence nor the creation of a new splice site (BP4); however, the residue altered (Ala75) is conserved through zebrafish. Thus, BP7 is not met. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00117 (21/17954 alleles) in the East Asian population, which is higher than the ClinGen CCDS VCEP’s threshold for BS1 (>0.001), and therefore meets this criterion (BS1). There is a ClinVar entry for this variant (Variation ID: 137433). In summary, this variant meets the crietria to be classified as likely benign for GAMT deficiency. GAMT-specific criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (CCDS VCEP): BS1, BP4. (Classification approved by the ClinGen CCDS VCEP on March 9, 2023).

Met criteria codes

• BP4: No impact on splicing predicted by SpliceAI (BP4).
• BS1: The highest population minor allele frequency in gnomAD v2.1.1 is 0.00117 (21/17954 alleles) in the East Asian population, which is higher than the ClinGen CCDS VCEP’s threshold for BS1 (>0.001), and therefore meets this criterion (BS1).

Not Met criteria codes

• BP7: Synonymous (silent) variant for which splicing prediction algorithms (SpliceAI, varSEAK) predict no impact to the splice consensus sequence nor the creation of a new splice site; however, the residue altered (Ala75) is conserved through zebrafish.