Variant: NM_000156.6(GAMT):c.655G>A (p.Asp219Asn)

CA314786

205569 (ClinVar)

Gene: GAMT

Condition: guanidinoacetate methyltransferase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 20230fce-2268-44ff-b7e7-2efcca6bf325

Approved on: 2024-09-11

Published on: 2024-09-12

HGVS expressions

NM_000156.6:c.655G>A
NM_000156.6(GAMT):c.655G>A (p.Asp219Asn)
NC_000019.10:g.1397415C>T
CM000681.2:g.1397415C>T
NC_000019.9:g.1397414C>T
CM000681.1:g.1397414C>T
NC_000019.8:g.1348414C>T
NG_008283.1:g.18532C>T
NG_009785.1:g.9139G>A
ENST00000252288.8:c.655G>A
ENST00000640164.1:n.488G>A
ENST00000640762.1:c.586G>A
ENST00000252288.6:c.655G>A
NM_000156.5:c.655G>A

Uncertain Significance

• Not Met criteria codes: PP3 PM2 PM5 BS1 BP4

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.655G>A variant in GAMT is a missense variant that is predicted to cause the substitution of aspartate for asparagine at amino acid 219 (p.Asp219Asn). 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 0.0004834 (29/59986 alleles) in the Admixed American population (none of the population data codes are met). The computational predictor REVEL gives a score of 0.293 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: 205569). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 2.0.0): no criteria met. (Classification approved by the ClinGen Creatine Deficiency Syndromes Variant Curation Expert Panel on September 11, 2024).

Not Met criteria codes

• PP3: The computational predictor REVEL gives a score of 0.293 which is neither above nor below the thresholds predicting a damaging (>0.644) or benign (<0.29) impact on GAMT function.
• PM2: The highest population minor allele frequency in gnomAD v4.1.0. is 0.0004834 (29/59986 alleles) in the Admixed American population (none of the population data codes are met).
• PM5: c.657C>A (p.Asp219Glu) is a VUS in ClinVar (ID: 1754277)
• BS1: The highest population minor allele frequency in gnomAD v4.1.0. is 0.0004834 (29/59986 alleles) in the Admixed American population (none of the population data codes are met).
• BP4: The computational predictor REVEL gives a score of 0.293 which is neither above nor below the thresholds predicting a damaging (>0.644) or benign (<0.29) impact on GAMT function.