NM_000156.6:c.623G>C

CA9043555

Gene: GAMT

Condition: guanidinoacetate methyltransferase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: e89e7d7a-db98-4496-85e0-5e86e6cfeab3

Approved on: 2025-03-18

Published on: 2025-03-20

HGVS expressions

NM_000156.6:c.623G>C
NC_000019.10:g.1397447C>G
CM000681.2:g.1397447C>G
NC_000019.9:g.1397446C>G
CM000681.1:g.1397446C>G
NC_000019.8:g.1348446C>G
NG_008283.1:g.18564C>G
NG_009785.1:g.9107G>C
ENST00000252288.8:c.623G>C
ENST00000640164.1:n.456G>C
ENST00000640762.1:c.554G>C
ENST00000252288.6:c.623G>C
NM_000156.5:c.623G>C

Likely Pathogenic

• Met criteria codes: PP3 PM3_Supporting PM2_Supporting PP4_Strong PS3_Supporting

• Not Met criteria codes: 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.623G>C variant in GAMT is a missense variant predicted to cause substitution of arginine by proline at amino acid 208 (p.Arg208Pro). This variant is absent in gnomAD v4.1.0. (PM2_Supporting). It has been reported in homozygosity in one individual with clinical symptoms consistent with GAMT deficiency (severe intellectual impairment, intractable seizures, movement disorder), deficienct GAMT activity, and reduction of creatine on brain MRS, who showed clinical improvement on dietary treatment (PMID 24415674, 29506905) (PM3_Supporting, PP4_Strong). When expressed in GAMT-deficient fibroblasts, the variant resulted in ~4% wild type GAMT activity (PMID 24415674) (PS3_Supporting). The computational predictor REVEL gives a score of 0.751, which is in the range (0.644-0.773) that predicts impact to GAMT function at the supporting level (Pejaver et al, 2022, PMID: 36413997) (PP3). Two additional missense variants at this amino acid position have been reported; c.623G>A (p.Arg208His) (ClinVarID: 577478), and c.622C>T (p.Arg208Cys) (ClinVar ID: 544261). Both of these variants have been classified as variants of uncertain significance by the ClinGen CCDS VCEP. There is no ClinVar entry for this variant. In summary, this variant meets the criteria to be classified as likely pathogenic for GAMT deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 2.0.0): PP4_Strong, PP3, PS3_Supporting, PM2_Supporting, PM3_Supporting. (Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel on March 18, 2025)

Met criteria codes

• PP3: The computational predictor REVEL gives a score of 0.751, which is in the range (0.644-0.773) that predicts impact to GAMT function at the supporting level (Pejaver et al, 2022, PMID: 36413997) (PP3).
• PM3_Supporting: One individual with symptoms consistent with GAMT deficiency is homozygous for the variant (0.5 points) (PMID: 24415674) (PM3_Supporting).
• PM2_Supporting: This variant is absent in gnomAD v4.1.0. (PM2_Supporting).
• PP4_Strong: One patient has been reported with clinical symptoms consistent with GAMT deficiency (severe intellectual impairment, intractable seizures, movement disorder), deficient GAMT activity, and reduction of creatine on brain MRS (PMID 24415674) (PP4_Strong).
• PS3_Supporting: When expressed in GAMT-deficient fibroblasts, the variant resulted in ~4% wild type GAMT activity (PMID 24415674).

Not Met criteria codes

• PM5: Two additional missense variants at this amino acid position have been reported; c.623G>A (p.Arg208His) (ClinVarID: 577478), and c.622C>T (p.Arg208Cys) (ClinVar ID: 544261). Both of these variants have been classified as variants of uncertain significance by the ClinGen CCDS VCEP.