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]
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Variant: NM_000156.6(GAMT):c.114C>T (p.Gly38=)

CA504731636

1305363 (ClinVar)

Gene: GAMT
Condition: guanidinoacetate methyltransferase deficiency
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 07773611-51a4-431b-afbf-2c92af74fc5e

HGVS expressions

NM_000156.6:c.114C>T
NM_000156.6(GAMT):c.114C>T (p.Gly38=)
NC_000019.10:g.1401363G>A
CM000681.2:g.1401363G>A
NC_000019.9:g.1401362G>A
CM000681.1:g.1401362G>A
NC_000019.8:g.1352362G>A
NG_009785.1:g.5191C>T
ENST00000252288.8:c.114C>T
ENST00000447102.8:c.114C>T
ENST00000640762.1:c.112+2C>T
ENST00000252288.6:c.114C>T
ENST00000447102.7:c.114C>T
NM_000156.5:c.114C>T
NM_138924.2:c.114C>T
NM_138924.3:c.114C>T

Likely Pathogenic

Met criteria codes 4
PP3 PM3 PM2_Supporting PP4_Strong

Evidence Links 0

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.114C>T (p.Gly38=) variant in GAMT is a synonymous (silent) variant. The computational splicing predictor SpliceAI gives a score of 0.98 for donor gain, predicting that the variant activates a cryptic splice site within exon 1 of GAMT (PP3). This variant has been reported in an individual with GAMT deficiency (PMID: 37305710). This individual was compound heterozygous for this variant and a variant that has been classified as likely pathogenic variant by the ClinGen CCDS VCEP, c.328-1G>A (ClinVar ID 844968), and confirmed in trans by parental testing (PMID: 37305710). This individual had elevated guanidinoacetate levels in plasma and significantly decreased creatine peak on brain MRS (PP4_Strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 1305363). In summary, this variant meets the criteria to be classified as likely pathogenic for GAMT 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, PM3, PP3, PP4_Strong. (Classification approved by the ClinGen CCDS VCEP on April 26, 2024)
Met criteria codes
PP3
The computational splicing predictor SpliceAI gives a score of 0.98 for donor gain, predicting that the variant activates a cryptic splice site within exon 1 of GAMT (PP3).
PM3
This individual was compound heterozygous for this variant and a likely pathogenic variant, c.328-1G>A (ClinVar ID 844968), which were confirmed in trans by parental testing (PMID: 37305710) (PM3). (1pt)
PM2_Supporting
This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
PP4_Strong
This individual had elevated GAA in plasma and significantly decreased creatine peak on brain MRS (PP4_Strong).
Approved on: 2024-04-26
Published on: 2024-06-12
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