Variant: NM_000156.6(GAMT):c.299_311dup (p.Arg105fs)

CA340767

8302 (ClinVar)

Gene: GAMT

Condition: guanidinoacetate methyltransferase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: b134da76-0dcf-48dd-ae4e-1058f82a5e7e

Approved on: 2022-06-06

Published on: 2022-10-07

HGVS expressions

NM_000156.6:c.299_311dup
NM_000156.6(GAMT):c.299_311dup (p.Arg105fs)
NC_000019.10:g.1399811_1399823dup
CM000681.2:g.1399811_1399823dup
NC_000019.9:g.1399810_1399822dup
CM000681.1:g.1399810_1399822dup
NC_000019.8:g.1350810_1350822dup
NG_009785.1:g.6733_6745dup
ENST00000252288.8:c.299_311dup
ENST00000447102.8:c.299_311dup
ENST00000640762.1:c.230_242dup
ENST00000252288.6:c.299_311dup
ENST00000447102.7:c.299_311dup
NM_000156.5:c.299_311dup
NM_138924.2:c.299_311dup
NM_138924.3:c.299_311dup

Pathogenic

• Met criteria codes: PM3 PM2_Supporting PVS1 PP4_Strong

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

Evidence submitted by expert panel

Cerebral Creatine Deficiency Syndromes VCEP

The NM_000156.6:c.299_311dup (p. Arg105GlyfsTer26) in GAMT is a frameshift variant predicted to cause a premature stop codon in biologically relevant 3/6 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least 4 probands with biochemical and clinical features consistent with GAMT deficiency have been reported, including patients with elevated plasma guanidinoacetate, and absent creatine peak and evidence of guanidinoacetate peak on magnetic resonance spectroscopy (PMIDs 8651275, 19027335, 19388150, 23660394, 29506905) (PP4_Strong). These patients include one homozygote (with a homozygous affected sibling) (PMID 23234264; 0.5 points; possibly same patient reported in PMID 29506905); and a proband who is compound heterozygous for the variant and c.327G>A (pathogenic based on assessment by the ClinGen CCDS VCEP), confirmed in trans (PMID 8651275, 19027335, 24268530) (PM3). Another patient is compound heterozygous for the variant and c.233T>A (p.Val78Glu)(PMID 23660394), and another patient and her affected sibling are compound heterozygous for the variant and c.403G>A (p.Asp135Asn) (PMID 19388150), The in trans data from the latter patients will be used in the analysis of p.Val78Glu and p.Asp135Asn and is not included here to avoid circular logic (PM3_Strong). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001175 in the European non-Finnish population, which 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: 8302). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 1.1.0): PVS1, PM3, PP4_Strong, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).

Met criteria codes

• PM3: At least 4 probands with this variant and features consistent with GAMT deficiency have been reported including one homozygote (with a homozygous affected sibling) (PMID 23234264; 0.5 points; possibly same patient reported in PMID 29506905); a proband who is compound heterozygous for the variant and c.327G>A (pathogenic based on assessment by the ClinGen CCDS VCEP), confirmed in trans (PMID 8651275, 19027335, 24268530; 1 point). Another patient is compound heterozygous for the variant and c.233T>A (p.Val78Glu)(PMID 23660394), and another patient and her affected sibling are compound heterozygous for the variant and c.403G>A (p.Asp135Asn) (PMID 19388150), The in trans data from the latter patients will be used in the analysis of p.Val78Glu and p.Asp135Asn and is not included here to avoid circular logic. Total for PM3 is 1.5 points (PM3).
• PM2_Supporting: The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001175 in the European non-Finnish population, which is lower than the ClinGen CCDS VCEP's threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting).
• PVS1: The NM_000156.6:c.299_311dup (p. Arg105GlyfsTer26) in GAMT is a frameshift variant predicted to cause a premature stop codon in biologically relevant 3/6 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).
• PP4_Strong: At least 4 probands with biochemical and clinical features consistent with GAMT deficiency have been reported, including patients with two or more of the following – absent creatine peak and presence of GAc on MRA, GAMT deficiency liver, and elevated GAc with low creatine in urine and plasma. (PMIDs 8651275, 19027335, 19388150, 23660394, 29506905) (PP4_Strong).