Variant: NM_000156.6(GAMT):c.314G>A (p.Arg105Gln)

CA9043741

390894 (ClinVar)

Gene: GAMT

Condition: guanidinoacetate methyltransferase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: baac6d66-964b-46ad-8587-fdb3112cadfe

Approved on: 2025-03-13

Published on: 2025-03-14

HGVS expressions

NM_000156.6:c.314G>A
NM_000156.6(GAMT):c.314G>A (p.Arg105Gln)
NC_000019.10:g.1399806C>T
CM000681.2:g.1399806C>T
NC_000019.9:g.1399805C>T
CM000681.1:g.1399805C>T
NC_000019.8:g.1350805C>T
NG_009785.1:g.6748G>A
ENST00000252288.8:c.314G>A
ENST00000447102.8:c.314G>A
ENST00000640762.1:c.245G>A
ENST00000252288.6:c.314G>A
ENST00000447102.7:c.314G>A
NM_000156.5:c.314G>A
NM_138924.2:c.314G>A
NM_138924.3:c.314G>A

Likely Benign

• Met criteria codes: BP4 BS3_Supporting

• Not Met criteria codes: BS2 PM2 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.314G>A variant in GAMT is a missense variant predicted to cause the substitution of an arginine by a glutamine at amino acid position 105 (p.Arg105Gln). This variant has been previously reported in two individuals in the Exome Variant Server database, both of whom were heterozygous for the variant (PMID: 26003046) but, to our knowledge, it has not been reported among individuals with GAMT deficiency. The highest population minor allele frequency in gnomAD v4.1.0. is 0.0002374 (275/1158566 alleles; 1 homozygote) in the European (non-Finnish) population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), but due to the presence of a homozygote, the criterion was not applied. BS2 was not applied here to avoid double counting this evidence. Expression of the variant in HeLa cells resulted in GAMT enzyme activity similar to wild type GAMT (BS3_Supporting). The computational predictor REVEL gives a score of 0.14 which is below the threshold of 0.29, evidence that does not predict a damaging effect on GAMT function (BP4). There is a ClinVar entry for this variant (Variation ID: 390894). In summary, this variant meets the criteria to be classified as likely benign 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): BS3_Supporting, BP4. ((Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on March 13, 2025)

Met criteria codes

• BP4: The computational predictor REVEL gives a score of 0.14 which is below the threshold of 0.29, evidence that does not predict a damaging effect on GAMT function (BP4).
• BS3_Supporting: Expression of the variant in HeLa cells resulted in GAMT enzyme activity similar to wild type GAMT enzyme activity indicating that this variant does not impact protein function (PMID: 26003046) (BS3_Supporting).

Not Met criteria codes

• BS2: One homozygote in gnomAD v4.1.0 in the European non-Finnish population. The presence of the homozygote was used in order to not apply PM2_Supporting. BS2 is not applied here to avoid double counting this evidence.
• PM2: The highest population minor allele frequency in gnomAD v4.1.0. is 0.0002374 (275/1158566 alleles; 1 homozygote) in the European (non-Finnish) population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), but due to the presence of a homozygote, the criterion was not applied.
• PM5: c.313C>T (p.Arg105Trp) is classified as a VUS in ClinVar (ID: 431818)