Variant: NM_001482.3(GATM):c.1252T>C (p.Leu418=)

CA152946

129137 (ClinVar)

Gene: GATM

Condition: AGAT deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: d4eeb1ba-51cf-469b-b039-1c2ace854aec

Approved on: 2022-06-06

Published on: 2022-10-07

HGVS expressions

NM_001482.3:c.1252T>C
NM_001482.3(GATM):c.1252T>C (p.Leu418=)
NC_000015.10:g.45362129A>G
CM000677.2:g.45362129A>G
NC_000015.9:g.45654327A>G
CM000677.1:g.45654327A>G
NC_000015.8:g.43441619A>G
NG_011674.1:g.21654T>C
NG_011674.2:g.45189T>C
ENST00000396659.8:c.1252T>C
ENST00000674905.1:c.*214T>C
ENST00000675158.1:c.*152T>C
ENST00000675323.1:c.*1754T>C
ENST00000675701.1:c.1192T>C
ENST00000675974.1:n.3801T>C
ENST00000676090.1:c.*1983T>C
ENST00000396659.7:c.1252T>C
ENST00000558362.5:n.2908T>C
NM_001482.2:c.1252T>C
NM_001321015.1:c.865T>C
NM_001321015.2:c.865T>C

Benign

• Met criteria codes: BA1 BP7 BP4

• Not Met criteria codes: PM2

Expert Panel

Cerebral Creatine Deficiency Syndromes VCEP

Criteria Specification Information

Evidence submitted by expert panel

Cerebral Creatine Deficiency Syndromes VCEP

The NM_001482.3:c.1252T>C (p.Leu418=) variant in GATM is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by PhyloP (BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.9186 (18317/19940 alleles) in the East Asian population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.0005), and therefore meets this criterion (BA1). The computational splicing predictor SpliceAI gives a score of 0.0 for donor and acceptor loss suggesting that the variant has no impact on splicing, and the nucleotide is not highly conserved (BP4, BP7). There is a ClinVar entry for this variant (Variation ID: 129137). In summary, this variant meets the criteria to be classified as benign 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): BA1, BP4, BP7. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).

Met criteria codes

• BA1: gnomAD allele frequency is 53.69% with 45916 homozygotes
• BP7: No predicted impact on splicing by SpliceAI and varSEAK. Nucleotide weakly conserved (PhlyoP = 1.58)
• BP4: No predicted impact on splicing by SpliceAI and varSEAK.

Not Met criteria codes

• PM2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline