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]

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Variant: NM_138924.3:c.115A>G

CA402998134

Gene: GAMT

Condition: guanidinoacetate methyltransferase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: c4f27b5f-831e-4fe5-987b-293447d83b40

Approved on: 2023-12-14

Published on: 2023-12-14

HGVS expressions

NM_138924.3:c.115A>G

NC_000019.10:g.1401362T>C

CM000681.2:g.1401362T>C

NC_000019.9:g.1401361T>C

CM000681.1:g.1401361T>C

NC_000019.8:g.1352361T>C

NG_009785.1:g.5192A>G

ENST00000252288.8:c.115A>G

ENST00000447102.8:c.115A>G

ENST00000640762.1:c.112+3A>G

ENST00000252288.6:c.115A>G

ENST00000447102.7:c.115A>G

NM_000156.5:c.115A>G

NM_138924.2:c.115A>G

NM_000156.6:c.115A>G

Likely Pathogenic

PM3_Supporting PM2_Supporting PP3 PP4_Strong

PM5

Evidence Links 0

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Cerebral Creatine Deficiency Syndromes VCEP

NM_000156.6(GAMT):c.115A>G (p.Lys39Glu) is a missense variant in the first exon of the GAMT gene. This variant is absent from gnomAD v4 (PM2_Supporting). The computational predictor REVEL gives a score of 0.721, which meets the threshold set in Pejaver et al. 2022 (PMID:36413997) for (PP3_Met). The c.115A>G(p.Lys39Glu) variant was identified in a proband alongside the pathogenic variant c.328-2A>G (PMID:3730571). Phase analysis was unclear, meeting the Cerebral Creatine Deficiency Syndromes metric for PM3_Supporting. This same proband is reported with moderate global developmental delay. Dried blood spot analysis measured increased GAA with significantly reduced creatine (2 points), and the patient has a significantly decreased creatine peak via MRS (3 points) (PMID:37305710) (PP4_Strong). In summary, the NM_000156.6(GAMT):c.115A>G (p.Lys39Glu) variant meets the criteria to be classified as Likely Pathogenic for Creatine Transporter 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). PM2_Supporting, PP4_Strong, PP3, PM3_Supporting. (Classification approved by the ClinGen CCDS VCEP on December 14, 2023).

PM3_Supporting

The c.115A>G(p.Lys39Glu) variant was identified in a proband alongside the pathogenic variant c.328-2A>G (PMID:3730571). Phase analysis was unclear, meeting the Cerebral Creatine Deficiency Syndromes metric for PM3_Supporting.

PM2_Supporting

This variant is absent from gnomAD v4 (PM2_Supporting).

PP3

The computational predictor REVEL gives a score of 0.721, which meets the threshold set in Pejaver et al. 2022 (PMID:36413997) for PP3.

PP4_Strong

One male proband reported with moderate global developmental delay. Dried blood spot analysis measured increased GAA with significantly reduced creatine (2 points), patient has significantly decreased creatine peak via MRS (3 points). (PMID:37305710) (PP4_Strong).

PM5

Another missense variant (c.115A>C p.Lys39Gln) in the same codon has been classified as of uncertain significance by a clinical lab, but it was absent literature evidence (ClinVar ID:1051517) (PM5 not met).

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