Variant: NM_000156.6(GAMT):c.491G>A (p.Gly164Asp)

CA314807

205581 (ClinVar)

Gene: GAMT

Condition: guanidinoacetate methyltransferase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: fd7e045d-f8c5-457a-bfef-c535608351ea

Approved on: 2024-09-11

Published on: 2024-09-12

HGVS expressions

NM_000156.6:c.491G>A
NM_000156.6(GAMT):c.491G>A (p.Gly164Asp)
NC_000019.10:g.1398995C>T
CM000681.2:g.1398995C>T
NC_000019.9:g.1398994C>T
CM000681.1:g.1398994C>T
NC_000019.8:g.1349994C>T
NG_009785.1:g.7559G>A
ENST00000252288.8:c.491G>A
ENST00000447102.8:c.491G>A
ENST00000591788.3:c.174G>A
ENST00000640164.1:n.324G>A
ENST00000640762.1:c.422G>A
ENST00000252288.6:c.491G>A
ENST00000447102.7:c.491G>A
ENST00000591788.2:c.176G>A
NM_000156.5:c.491G>A
NM_138924.2:c.491G>A
NM_138924.3:c.491G>A

Likely Pathogenic

• Met criteria codes: PM3 PP3_Moderate PP4 PM2_Supporting

• Not Met criteria codes: PM5

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 2.0.0

Evidence submitted by expert panel

Cerebral Creatine Deficiency Syndromes VCEP

The NM_000156.6:c.491G>A variant in GAMT is a missense variant predicted to cause the substitution of a glycine by an aspartate at amino acid position 164 (p.Gly164Asp). This variant has been previously reported in one patient who had elevated plasma guanidinoacetate levels on two occasions (PP4) and was compound heterozygous for the variant and a pathogenic variant in GAMT, c.522G>A (p.Trp174Ter, ClinVar ID: 205584), confirmed in trans by parental testing (PM3). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00001667 (1/59992 alleles) in the Admixed American population, which is lower 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 0.919, evidence that correlates with impact to GAMT function (PP3_Moderate applied for REVEL score range 0.773-0.932). There is a ClinVar entry for this variant (Variation ID: 203539). In summary, this variant meets the criteria to be classified as likely pathogenic 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 2.0.0): PM3, PP4, PP3_Moderate, PM2_Supporting. (Classification approved by the ClinGen Creatine Deficiency Syndromes Variant Curation Expert Panel on September 11, 2024).

Met criteria codes

• PM3: This variant has been detected in 1 individual with GAMT deficiency. They were compound heterozygous for the variant and a pathogenic variant [c.522G>A (p.Trp174Ter); ClinVar ID: 205584] and confirmed in trans by parental testing (PMID : 23660394) Total 1 point (PM3).
• PP3_Moderate: The computational predictor REVEL gives a score of 0.919, evidence that correlates with impact to GAMT function (PP3_Moderate applied for REVEL score range 0.773-0.932).
• PP4: One patient with two elevated plasma guanidinoacetate levels has been reported (PMID: 23660394) (PP4).
• PM2_Supporting: The highest population minor allele frequency in gnomAD v4.1.0. is 0.00001667 (1/59992 alleles) in the Admixed American population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting).

Not Met criteria codes

• PM5: c.491G>T (p.Gly164Val) is VUS in ClinVar (ID: 1312507)