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.48C>A

CA402998364

2412845 (ClinVar)

Gene: GAMT

Condition: guanidinoacetate methyltransferase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 3a761134-fdab-4d0f-a4da-dcb7b040a030

HGVS expressions

NM_138924.3:c.48C>A

NC_000019.10:g.1401429G>T

CM000681.2:g.1401429G>T

NC_000019.9:g.1401428G>T

CM000681.1:g.1401428G>T

NC_000019.8:g.1352428G>T

NG_009785.1:g.5125C>A

ENST00000252288.8:c.48C>A

ENST00000447102.8:c.48C>A

ENST00000640762.1:c.48C>A

ENST00000252288.6:c.48C>A

ENST00000447102.7:c.48C>A

NM_000156.5:c.48C>A

NM_138924.2:c.48C>A

NM_000156.6:c.48C>A

NM_000156.6(GAMT):c.48C>A (p.Cys16Ter)

Pathogenic

PM3 PVS1 PP4_Strong

PM2

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.48C>A (p.Cys16Ter) variant in GAMT is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 1/6, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD v2.1.1 but coverage of this region is <20X and therefore PM2_Supporting is not met. First cousins who are homozygous for the variant (PMID 31559727), and siblings who are compound heterozygous for the variant and another variant in GAMT that has been classified as pathogenic by the ClinGen CCDS VCEP, c.327G>A, phase unknown, have been reported (PMID: 24268530) (PM3). These individuals all had clinical symptoms consistent with GAMT deficiency; in one of them elevated guanidinoacetate values were documented in urine and creatine peak was "sharply" decreased on MRS (PP4_Strong). There is a ClinVar entry for this variant (Variation ID: 2412845). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency. GAMT-specific criteria met, as specified by the ClinGen CCDS Variant Curation Expert Panel (Specifications Version 1.1.0), PVS1, PP4_Strong, PM3. (CLassification approved by the ClinGen CCDS VCEP, August 8, 2023)

PM3

First cousins who are homozygous for the variant (PMID 31559727; 0.5 points), and siblings who are compound heterozygous for the variant and another variant in GAMT that has been classified as pathogenic by the ClinGen CCDS VCEP, c.327G>A, phase unknown, have been reported (PMID: 24268530; 0.5 points). Total 1 point (PM3).

PVS1

The NM_000156.6:c.48C>A (p.Cys16Ter) variant in GAMT is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 1/6 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).

PP4_Strong

First cousins, who are homozygous for the variant, have been reported. One of these individuals had elevated guanidinoacetate in urine and decreased creatine peak on MRS (PP4_Strong).

PM2

This variant is absent in gnomAD v2.1.1 but coverage of this region is <20X and therefore PM2_Supporting is not met.

Approved on: 2023-08-08

Published on: 2023-09-13

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