Variant: NM_000156.6(GAMT):c.298C>T (p.Arg100Trp)

CA314802

205579 (ClinVar)

Gene: GAMT

Condition: guanidinoacetate methyltransferase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: b105043f-2ff1-49ab-9dee-6310ae7abdd0

Approved on: 2025-03-18

Published on: 2025-03-20

HGVS expressions

NM_000156.6:c.298C>T
NM_000156.6(GAMT):c.298C>T (p.Arg100Trp)
NC_000019.10:g.1399822G>A
CM000681.2:g.1399822G>A
NC_000019.9:g.1399821G>A
CM000681.1:g.1399821G>A
NC_000019.8:g.1350821G>A
NG_009785.1:g.6732C>T
ENST00000252288.8:c.298C>T
ENST00000447102.8:c.298C>T
ENST00000640762.1:c.229C>T
ENST00000252288.6:c.298C>T
ENST00000447102.7:c.298C>T
NM_000156.5:c.298C>T
NM_138924.2:c.298C>T
NM_138924.3:c.298C>T

Benign

• Met criteria codes: BS2 BS1

• Not Met criteria codes: BP4 PP3 PM5

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.298C>T variant in GAMT is a missense variant that is predicted to cause the substitution of an arginine by a tryptophan at amino acid position 100 (p.Arg100Trp). To our knowledge, this variant has not been reported among individuals with GAMT deficiency and results of functional studies are unavailable. The GrpMax filtering allele frequency (95th % confidence) in gnomAD v4.1.0. is 0.002776 in the South Asian population, which is higher than the ClinGen CCDS VCEP’s threshold for BS1 (>0.001), and therefore meets this criterion (BS1). There are 2 homozygotes in gnomAD v4.1.0. Because GAMT deficiency is a severe, pediatric-onset disorder, this data supports the benignity of the variant (BS2). The computational predictor REVEL gives a score of 0.331 which is neither above nor below the thresholds predicting a damaging (≥0.644) or benign (<0.29) impact on GAMT function. There is a ClinVar entry for this variant (Variation ID: 205579). In summary, this variant meets the criteria to be classified as benign 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): BS1, BS2. (Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel on March 18, 2025)

Met criteria codes

• BS2: There are 2 homozygotes in gnomAD v4.1.0.
• BS1: The GrpMax filtering allele frequency in gnomAD v4.1.0. is 0.002776 in the South 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

• BP4: The computational predictor REVEL gives a score of 0.331 which is neither above nor below the thresholds predicting a damaging (≥0.644) or benign (<0.29) impact on GAMT function.
• PP3: The computational predictor REVEL gives a score of 0.331 which is neither above nor below the thresholds predicting a damaging (≥0.644) or benign (<0.29) impact on GAMT function.
• PM5: Arg100Gln has conflicting interpretations in ClinVar (ID: 2145645)