Variant: NM_001482.3(GATM):c.1237C>T (p.Arg413Trp)

CA392254708

598112 (ClinVar)

Gene: GATM

Condition: AGAT deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 966c6aa8-1d86-4df7-a744-3d2806a9fdb6

Approved on: 2024-08-20

Published on: 2024-09-20

HGVS expressions

NM_001482.3:c.1237C>T
NM_001482.3(GATM):c.1237C>T (p.Arg413Trp)
NC_000015.10:g.45362144G>A
CM000677.2:g.45362144G>A
NC_000015.9:g.45654342G>A
CM000677.1:g.45654342G>A
NC_000015.8:g.43441634G>A
NG_011674.1:g.21639C>T
NG_011674.2:g.45174C>T
ENST00000396659.8:c.1237C>T
ENST00000674905.1:c.*199C>T
ENST00000675158.1:c.*137C>T
ENST00000675323.1:c.*1739C>T
ENST00000675701.1:c.1177C>T
ENST00000675974.1:n.3786C>T
ENST00000676090.1:c.*1968C>T
ENST00000396659.7:c.1237C>T
ENST00000558362.5:n.2893C>T
NM_001482.2:c.1237C>T
NM_001321015.1:c.850C>T
NM_001321015.2:c.850C>T

Likely Pathogenic

• Met criteria codes: PM5_Supporting PS3_Supporting PM3 PP4_Strong PM2_Supporting

• Not Met criteria codes: BP4 PP3

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 GATM Version 1

Evidence submitted by expert panel

Cerebral Creatine Deficiency Syndromes VCEP

The NM_001482.3:c.1237C>T variant in GATM is a missense variant predicted to cause the substitution of an arginine by a tryptophan at amino acid position 413 (p.Arg413Trp). This variant has been detected in one individual with AGAT deficiency who had low guanidinoacetate in plasma and low to low-normal creatine in plasma, as well as significantly decreased creatine peak on brain MRS (PMID 26490222) (PP4_Strong). This individual was compound heterozygous for the variant and a likely pathogenic variant (p.Arg413Gln, ClinVar ID: 2446451), and the variants were confirmed in trans by parental testing (PMID 23660394) (PM3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Expression of the variant in HeLa cells resulted in 0% wild type AGAT activity (PMID: 27233232), indicating that this variant may impact protein function (PS3_Supporting). The computational predictor REVEL gives a score of 0.585 which is neither above nor below the thresholds predicting a damaging (>0.75) or benign (<0.15) impact on AGAT function.Another missense variant c.1238G>A, (p.Arg413Gln) (PMID: 23660394, 26490222, 27233232) in the same codon has been classified as likely pathogenic for AGAT deficiency by the ClinGen CCDS VCEP (ClinVar ID: 2446451) (PM5_Supporting). There is a ClinVar entry for this variant (Variation ID: 598112). In summary, this variant meets the criteria to be classified as likely pathogenic for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PP4_Strong, PM3, PM2_Supporting, PS3_Supporting, PM5_Supporting. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on August 20, 2024).

Met criteria codes

• PM5_Supporting: GATM c.1238G>A; p.Arg413Gln is likely pathogenic per CCDS VCEP guidelines (PP4_Strong, PM2_Supporting, PS3_Supporting) (PMIDs 23660394, 26490222, 27233232)
• PS3_Supporting: Functional analysis of GATM enzymatic activity of the p.Arg413Trp variant expressed in HeLa cells demonstrates 0% WT activity (PMID: 27233232).
• PM3: One individual is compound heterozygous for c.1237C>T (p.Arg413Trp) and a variant that has been classified as likely pathogenic by the ClinGen CCDS VCEP, c.1238G>A (p.Arg413Gln); the variants were confirmed to be in trans by parental testing (PMID 23660394, 26490222). 1 point (PM3)
• PP4_Strong: Found in a patient with absent brain creatine by MRS, plasma GAA <0.01% normal, plasma creatine <2% normal (PMID: 26490222)
• PM2_Supporting: Absent from gnomAD v2.1.1 (PM2_Supporting).

Not Met criteria codes

• BP4: REVEL score is 0.585
• PP3: REVEL score is 0.585