Variant: NM_138924.3:c.152A>C

CA402998053

2138184 (ClinVar)

Gene: GAMT

Condition: guanidinoacetate methyltransferase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 666f3a4c-7076-43ec-8c81-965928812a1e

Approved on: 2023-09-12

Published on: 2023-09-13

HGVS expressions

NM_138924.3:c.152A>C
NC_000019.10:g.1401325T>G
CM000681.2:g.1401325T>G
NC_000019.9:g.1401324T>G
CM000681.1:g.1401324T>G
NC_000019.8:g.1352324T>G
NG_009785.1:g.5229A>C
ENST00000252288.8:c.152A>C
ENST00000447102.8:c.152A>C
ENST00000640762.1:c.112+40A>C
ENST00000252288.6:c.152A>C
ENST00000447102.7:c.152A>C
NM_000156.5:c.152A>C
NM_138924.2:c.152A>C
NM_000156.6:c.152A>C
NM_000156.6(GAMT):c.152A>C (p.His51Pro)

Likely Pathogenic

• Met criteria codes: PM3 PP3 PP4_Strong PM2_Supporting PS3_Supporting

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:c.152A>C variant in GAMT is a missense variant that is predicted to result in the substitution of histidine by proline at amino acid 51 (p.His51Pro). One proband has been reported with mild developmental delay, anti-epileptic drug responsive seizures, and autistic features, with a normal brain MRI. This individual had elevated guanidinoacetate in urine and, on MRS, creatine peak was partially absent and guanidinoacetate was absent (PMID: 15108290, 24415674) (PP4_Strong). This individual is compound heterozygous for the variant and another variant in GAMT that has been classified as pathogenic by the ClinGen CCDS VCEP, c.526dupG. The variants were confirmed to be in trans by parental testing (PM3). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). When the variant was expressed in a primary GAMT-deficient human fibroblast cell line, no detectable expression could be seen on Western blot and the GAMT activity was very low (<4%)(PMID 24415674) (PS3_Supporting). The computational predictor REVEL gives a score of 0.814 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for GAMT deficiency. GAMT-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Cerebral Creatine Deficiencies VCEP (Specifications Version 1.1.0): PP4_Strong, PM3, PP3, PS3_Supporting, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP, Sept 12, 2023)

Met criteria codes

• PM3: One patient has been reported who meets the CCDS VCEP's PP4 specifications and is compound heterozygous for the variant and a pathogenic variant in GAMT, confirmed in trans. 1 point was given towards PM3, meeting PM3.
• PP3: The computational predictor REVEL gives a score of 0.814 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3).
• PP4_Strong: One proband has been reported with mild developmental delay, anti-epileptic drug responsive seizures, and autistic features, with a normal brain MRI. This individual had elevated guanidinoacetate in urine, 1.1-12 x normal (1 point), and on MRS, creatine peak was partially absent and guanidinoacetate was absent (2 points) (PMID: 15108290, 24415674) (PP4_Strong).
• PM2_Supporting: This variant is absent in gnomAD v2.1.1 (PM2_Supporting).
• PS3_Supporting: When the variant was expressed in a primary GAMT-deficient human fibroblast cell line (homozygous for a frameshift mutation), no detectable expression could be seen on Western blot and the GAMT activity was very low (<4%)(PMID 24415674) (PS3_Supporting).