Variant: NM_000156.6(GAMT):c.11_36dup (p.Gly13fs)

CA631301057

858462 (ClinVar)

Gene: GAMT

Condition: guanidinoacetate methyltransferase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 46c2c665-fd6b-4423-9f76-dc50e04e6fc7

Approved on: 2023-09-12

Published on: 2023-09-13

HGVS expressions

NM_000156.6:c.11_36dup
NM_000156.6(GAMT):c.11_36dup (p.Gly13fs)
NC_000019.10:g.1401447_1401472dup
CM000681.2:g.1401447_1401472dup
NC_000019.9:g.1401446_1401471dup
CM000681.1:g.1401446_1401471dup
NC_000019.8:g.1352446_1352471dup
NG_009785.1:g.5088_5113dup
ENST00000252288.8:c.11_36dup
ENST00000447102.8:c.11_36dup
ENST00000640762.1:c.11_36dup
ENST00000252288.6:c.11_36dup
ENST00000447102.7:c.11_36dup
NM_000156.5:c.11_36dup
NM_138924.2:c.11_36dup
NM_138924.3:c.11_36dup

Pathogenic

• Met criteria codes: PM3_Supporting PVS1 PP4_Strong

• Not Met criteria codes: PM2

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

Evidence submitted by expert panel

Cerebral Creatine Deficiency Syndromes VCEP

The NM_000156.6(GAMT):c.11_36dup (p.Gly13ProfsTer38) variant in GAMT (also reported as c.36_c.37ins26) is a frameshift 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. However, the read depth is <20X at this position and therefore allele frequency data cannot be accurately assessed. Three individuals with biochemical and clinical features consistent with GAMT deficiency have been described including two with reduced creatine peak and guanidinoacetate (GAc) peak on MRS as well as elevated GAc in serum (PMID 19027335, 23660394, 24415674, 29506905) and one with deficient GAMT activity in fibroblasts (PMID 24415674) (PP4_Strong). These individuals are all compound heterozygous for the variant and a second variant in GAMT, phase unknown, including c.327G>A (PMID 19027335, 23660394; pathogenic based on assessment with the ClinGen CCDS VCEP; 0.5 points), c.133T>A (p.Trp45Arg), and c.439C>T (p.His147Tyr). The in trans data for the patients with c.133T>A (p.Trp45Arg) and c.439C>T (p.His147Tyr) will be used in the assessment of those variants and is not included here in order to avoid circular logic (PM3_Supporting). There is a ClinVar entry for this variant (Variation ID: 858462). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency. GAMT-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Cerebral Creatine Deficiencies VCEP (Specifications Version 1.1.0): PVS1, PP4_Strong, PM3_Supporting. (Classification approved by the ClinGen CCDS VCEP, September 12, 2023)

Met criteria codes

• PM3_Supporting: Three individuals with GAMT deficiency and this variant have been reported. These patients are all compound heterozygous for the variant and a second variant in GAMT, phase unknown, including c.327G>A (PMID 19027335, 23660394; pathogenic based on assessment with the ClinGen CCDS VCEP; 0.5 points), c.133T>A (p.Trp45Arg), and c.439C>T (p.His147Tyr). The in trans data for the patients with c.133T>A (p.Trp45Arg) and c.439C>T (p.His147Tyr) will be used in the assessment of those variants and is not included here in order to avoid circular logic (PM3_Supporting).
• PVS1: The NM_000156.6(GAMT):c.11_36dup (p.Gly13ProfsTer38) variant in GAMT (also reported as c.36_c.37ins26) is a frameshift 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: Three individuals with biochemical and clinical features consistent with GAMT deficiency have been described including two with reduced creatine peak and guanidinoacetate (GAc) peak on MRS as well as elevated GAc in serum (PMID 19027335, 23660394, 24415674, 29506905) and one with deficient GAMT activity in fibroblasts (PMID 24415674) (PP4_Strong).

Not Met criteria codes

• PM2: This variant is absent in gnomAD v2.1.1. However, the read depth is <20X at this position and therefore allele frequency data cannot be accurately assessed.