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.522G>C

CA402994365

2421360 (ClinVar)

Gene: GAMT

Condition: guanidinoacetate methyltransferase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: dc7ae64a-de29-424f-88bd-3984d1cf1a01

Approved on: 2023-12-12

Published on: 2023-12-12

HGVS expressions

NM_138924.3:c.522G>C

NC_000019.10:g.1398964C>G

CM000681.2:g.1398964C>G

NC_000019.9:g.1398963C>G

CM000681.1:g.1398963C>G

NC_000019.8:g.1349963C>G

NG_009785.1:g.7590G>C

ENST00000252288.8:c.522G>C

ENST00000447102.8:c.522G>C

ENST00000591788.3:c.205G>C

ENST00000640164.1:n.355G>C

ENST00000640762.1:c.453G>C

ENST00000252288.6:c.522G>C

ENST00000447102.7:c.522G>C

ENST00000591788.2:c.207G>C

NM_000156.5:c.522G>C

NM_138924.2:c.522G>C

NM_000156.6:c.522G>C

NM_000156.6(GAMT):c.522G>C (p.Trp174Cys)

Uncertain Significance

PP3 PM2

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

The NM_000156.6:c.522G>C variant in GAMT is a missense variant predicted to cause substitution of a tryptophan by cysteine at amino acid 174 (p.Trp174Cys). To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v4.0. is 0.00002227 (1/44900 alleles) in the East Asian population, which lower is than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.813 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3). There is a ClinVar entry for this variant (Variation ID: 2421360. 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 1.1.0): PP3, PM2_Supporting. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on December 12, 2023).

PP3

The computational predictor REVEL gives a score of 0.813 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3).

PM2

The highest population minor allele frequency in gnomAD v4.0. is 0.00002227 (1/44900 alleles) in the East Asian population, which lower is than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting).

PM5

Two different missense variants at the same codon, p.Trp174Arg (ClinVar ID: 1420866) and p.Trp174Leu (ClinVar ID: 966083), have been reported as VUS in ClinVar

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