Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • No ClinVar Id was directly found from the curated document
  • ClinVar Id was derived from the Allele Registry.
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_138924.3:c.274A>G

CA402996427

2446453 (ClinVar)

Gene: GAMT
Condition: guanidinoacetate methyltransferase deficiency
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: a430849d-26c4-42f2-a413-c79e51cad973
Approved on: 2023-01-12
Published on: 2023-01-25

HGVS expressions

NM_138924.3:c.274A>G
NC_000019.10:g.1399846T>C
CM000681.2:g.1399846T>C
NC_000019.9:g.1399845T>C
CM000681.1:g.1399845T>C
NC_000019.8:g.1350845T>C
NG_009785.1:g.6708A>G
ENST00000252288.8:c.274A>G
ENST00000447102.8:c.274A>G
ENST00000640762.1:c.205A>G
ENST00000252288.6:c.274A>G
ENST00000447102.7:c.274A>G
NM_000156.5:c.274A>G
NM_138924.2:c.274A>G
NM_000156.6:c.274A>G
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Uncertain Significance

Met criteria codes 5
PP3 PP4 PS3_Supporting PM2_Supporting PM3_Supporting

Evidence Links 1

Expert Panel

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
The NM_000156.6:c.274A>G variant in GAMT is a missense variant that is predicted to result in the substitution of asparagine by aspartate at amino acid 92 (p.Asn92Asp). This variant has been previously reported in one individual with elevated urine guanidinoacetate and low urine creatine who was homozygous for the variant (PMID: 19288536) (PP4, PM3_Supporting). This variant is absent from population databases (PM2_Supporting). The variant is predicted damaging by in-silico missense predictors (REVEL score 0.92) (PP3). This variant was shown to result in undetectable GAMT enzymatic activity when transfected into GAMT-deficient fibroblasts (PMID: 24415674) (PS3_Supporting). In summary, the clinical significance of the p.Asn92Asp variant is currently uncertain but tending towards likely pathogenic. GAMT-specific ACMG/AMP criteria applied: PS3_Supporting, PM2_Supporting, PM3_Supporting, PP3, PP4. (Classification approved by the ClinGen CCDS VCEP on January 12, 2023).
Met criteria codes
PP3
REVEL score 0.92, >0.75 cutoff for use of PP3
PP4
Identified in one individual who showed elevated urine GAA with low creatine (1pt, PP4_Supporting) (PMID: 19288536)
PS3_Supporting
PMID 24415674: Shown to result in <5% of wild-type GAMT enzyme activity in GAMT-deficient fibroblasts
PMID 24415674: Shown to result in <5% of wild-type GAMT enzyme activity in GAMT-deficient fibroblasts PubMed:24415674
PM2_Supporting
Absent in population databases
PM3_Supporting
Identified in one individual with guanidinoacetate methyltransferase deficiency, who was a homozygote for the variant (0.5pts) (PMID: 19288536)
Curation History
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