Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA152946

129137 (ClinVar)

Gene: GATM

Condition: AGAT deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

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

BA1 BP4 BP7

PM2

Evidence Links 0

Expert Panel

Cerebral Creatine Deficiency Syndromes VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

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).

BA1

gnomAD allele frequency is 53.69% with 45916 homozygotes

BP4

No predicted impact on splicing by SpliceAI and varSEAK.

BP7

No predicted impact on splicing by SpliceAI and varSEAK. Nucleotide weakly conserved (PhlyoP = 1.58)

PM2

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

Curation History

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