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_000156.6(GAMT):c.189G>C (p.Arg63=)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA9043767

288963 (ClinVar)

Gene: GAMT

Condition: guanidinoacetate methyltransferase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 2422ca9a-f7d4-4b9c-b558-d9b41e25a039

Approved on: 2024-10-08

Published on: 2024-10-25

HGVS expressions

NM_000156.6:c.189G>C

NM_000156.6(GAMT):c.189G>C (p.Arg63=)

NC_000019.10:g.1399931C>G

CM000681.2:g.1399931C>G

NC_000019.9:g.1399930C>G

CM000681.1:g.1399930C>G

NC_000019.8:g.1350930C>G

NG_009785.1:g.6623G>C

ENST00000252288.8:c.189G>C

ENST00000447102.8:c.189G>C

ENST00000640762.1:c.120G>C

ENST00000252288.6:c.189G>C

ENST00000447102.7:c.189G>C

NM_000156.5:c.189G>C

NM_138924.2:c.189G>C

NM_138924.3:c.189G>C

Uncertain Significance

BP7 BP4 PM2_Supporting

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 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Cerebral Creatine Deficiency Syndromes VCEP

The NM_000156.6:c.189G>C (p.Arg63=) variant in GAMT 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 (score -1.308) (BP4, BP7). To our knowledge, this variant has not been reported among individuals with GAMT deficiency and results of functional studies are unavailable. The GrpMax filtering allele frequency in gnomAD v4.1.0 is 0.0002424 in the African / African American population. This is lower than the ClinGen CCDS VCEP's threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 288963). In summary, this variant meets the criteria to be classified as a variant of uncertain significance 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 2.0.0): PM2_Supporting, BP4, BP7. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on October 8th, 2024).

BP7

BP4

No impact on splicing predicted by SpliceAI (all scores <0.1) (BP4).

PM2_Supporting

The GrpMax filtering allele frequency in gnomAD v4.1.0 is 0.0002424 in the African / African American population. This is lower than the ClinGen CCDS VCEP's threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting).

Curation History

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