Variant: NM_000156.6(GAMT):c.396C>A (p.Ile132=)

CA9043674

328348 (ClinVar)

Gene: GAMT

Condition: guanidinoacetate methyltransferase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 103b43b1-d256-422b-b514-4e3d7fb92a1d

Approved on: 2025-03-18

Published on: 2025-03-20

HGVS expressions

NM_000156.6:c.396C>A
NM_000156.6(GAMT):c.396C>A (p.Ile132=)
NC_000019.10:g.1399191G>T
CM000681.2:g.1399191G>T
NC_000019.9:g.1399190G>T
CM000681.1:g.1399190G>T
NC_000019.8:g.1350190G>T
NG_009785.1:g.7363C>A
ENST00000252288.8:c.396C>A
ENST00000447102.8:c.396C>A
ENST00000591788.3:c.79C>A
ENST00000640164.1:n.229C>A
ENST00000640762.1:c.327C>A
ENST00000252288.6:c.396C>A
ENST00000447102.7:c.396C>A
ENST00000591788.2:c.81C>A
NM_000156.5:c.396C>A
NM_138924.2:c.396C>A
NM_138924.3:c.396C>A

Likely Benign

• Met criteria codes: BS2 BP4 BP7

• Not Met criteria codes: BS1 PM2

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.396C>A variant in GAMT is a synonymous (silent) variant (p.Ile132=) with no predicted impact on splicing based on the computational predictor, SpliceAI (BP4, BP7). To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v4.1.0. is 0.0006575 (24/10058 alleles; one homozygote) in the Middle Eastern population, which is higher than the PM2_supporting threshold (<0.0004) and lower than the BS1 threshold (>0.001) set by the ClinGen CCDS VCEP (no population codes are met). While the allele frequency in the Ashkenazi Jewish population is higher, at 0.00304 (90/29608), this allele frequency data is not counted because the Ashkenazi Jewish population is not a continental population (see Ghosh et al, 2018, PMID: 30311383). There is a ClinVar entry for this variant (Variation ID: 328348). 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

• BS2: One homozygous individual was observed in gnomAD v4.1.0. Because GAMT deficiency is a severe, pediatric-onset disorder, this data supports the benignity of the variant (BS2).
• BP4: The computational predictor, SpliceAI, suggests that the variant has no impact on splicing (all scores = 0) (BP4)
• BP7: The NM_000156.6:c.396C>A variant in GAMT is a synonymous (silent) variant (p.Ile132=) with no predicted impact on splicing (BP7).

Not Met criteria codes

• BS1: The highest population minor allele frequency in gnomAD v4.1.0. is 0.0006575 (24/10058 alleles) in the Middle Eastern population, which is higher than the PM2_supporting threshold (<0.0004) and lower than the BS1 threshold (>0.001) set by the ClinGen CCDS VCEP (no population codes are met). While the allele frequency in the Ashkenazi Jewish population is higher at 0.00304 (90/29608), this data is not counted because the Ashkenazi Jewish population is not a continental population (see Ghosh et al, 2018, PMID: 30311383).
• PM2: The highest population minor allele frequency in gnomAD v4.1.0. is 0.0006575 (24/10058 alleles) in the Middle Eastern population, which is higher than the PM2_supporting threshold (<0.0004) and lower than the BS1 threshold (>0.001) set by the ClinGen CCDS VCEP (no population codes are met). While the allele frequency in the Ashkenazi Jewish population is higher at 0.00304 (90/29608), this data is not counted because the Ashkenazi Jewish population is not a continental population (see Ghosh et al, 2018, PMID: 30311383).