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.439C>T

CA402995088

Gene: GAMT

Condition: guanidinoacetate methyltransferase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 578f0aa4-5ea7-4f9b-a584-c6607d0cf64d

Approved on: 2023-03-23

Published on: 2023-03-29

HGVS expressions

NM_138924.3:c.439C>T

NC_000019.10:g.1399148G>A

CM000681.2:g.1399148G>A

NC_000019.9:g.1399147G>A

CM000681.1:g.1399147G>A

NC_000019.8:g.1350147G>A

NG_009785.1:g.7406C>T

ENST00000252288.8:c.439C>T

ENST00000447102.8:c.439C>T

ENST00000591788.3:n.122C>T

ENST00000640164.1:n.272C>T

ENST00000640762.1:c.370C>T

ENST00000252288.6:c.439C>T

ENST00000447102.7:c.439C>T

ENST00000591788.2:n.124C>T

NM_000156.5:c.439C>T

NM_138924.2:c.439C>T

NM_000156.6:c.439C>T

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

PM2_Supporting PS3_Supporting PM3_Supporting PP4_Moderate PP3

PM5

Evidence Links 1

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

The NM_000156.6:c.439C>T (p.His147Tyr) variant in GAMT has been identified in one individual with guanidinoacetate methyltransferase deficiency (PMID: 24415674). This variant was identified in 0.001470% (1/68016) of non-Finnish European chromosomes by the Genome Aggregation Database (gnomAD, dbSNP ID: rs1371496558) (PM2_Supporting). The patient previously reported was a compound heterozygote that carried a reported pathogenic variant, c.11_36dup (p.Gly13fs, ClinVar Variation ID: 858462), in unknown phase (PM3_Supporting). This individual showed reduced GAMT enzyme activity in fibroblasts (PP4_Moderate). The p.His147Tyr variant is a missense variant that is predicted damaging by in-silico missense predictors (REVEL score 0.888). This variant was shown to result in 4% of wild-type enzyme activity in GAMT-deficient fibroblasts (PMID: 24415674) (PS3_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for guanidinoacetate methyltransferase (GAMT) deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel (CCDS VCEP) (Specifications version 1.1.0): PS3_Supporting, PM2_Supporting, PM3_Supporting, PP3, PP4_Moderate (Richards 2015). (Classification approved by the ClinGen CCDS VCEP on March 23, 2023)

PM2_Supporting

Identified in 0.001470% (1/68016) of non-Finnish European chromosomes by the Genome Aggregation Database (gnomAD, dbSNP ID: rs1371496558)

PS3_Supporting

PMID: 24415674: shown to result in 4% of wild-type GAMT enzyme activity when expressed in GAMT-deficient fibroblasts

Variant shown to result in 4% of wild-type GAMT enzyme activity when expressed in GAMT-deficient fibroblasts PubMed:24415674

PM3_Supporting

PMID: 24415674: Identified in one individual who was a reported compound heterozygote who carried a pathogenic variant in unknown phase (c.11_36dup (p.Gly13fs), ClinVar Variation ID: 858462, PVS1, PM3_Supporting, PP4_Strong) (0.5pts).

PP4_Moderate

PMID: 24415674: Identified in one patient who showed deficient GAMT enzyme activity in cultured skin fibroblasts (3pts)

PP3

REVEL score 0.888, >0.75 cutoff for use of PP3

PM5

A different missense variant at the same amino acid residue, p.His147Gln has been previously reported as a variant of uncertain significance (ClinVar Variation ID: 450331).

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