Variant: NM_000156.6(GAMT):c.707G>C (p.Gly236Ala)

CA314836

205596 (ClinVar)

Gene: GAMT

Condition: guanidinoacetate methyltransferase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: a778869a-1616-4c03-9bc3-f083a641b642

Approved on: 2022-06-06

Published on: 2022-10-07

HGVS expressions

NM_000156.6:c.707G>C
NM_000156.6(GAMT):c.707G>C (p.Gly236Ala)
NC_000019.10:g.1397363C>G
CM000681.2:g.1397363C>G
NC_000019.9:g.1397362C>G
CM000681.1:g.1397362C>G
NC_000019.8:g.1348362C>G
NG_008283.1:g.18480C>G
NG_009785.1:g.9191G>C
ENST00000252288.8:c.707G>C
ENST00000640762.1:c.638G>C
ENST00000252288.6:c.707G>C
NM_000156.5:c.707G>C

Uncertain Significance

• Met criteria codes: BP4 PM2_Supporting

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.707G>C (p.Gly236Ala) variant in GAMT is a missense variant predicted to cause substitution of glycine by alanine at amino acid 236 (p.Gly236Ala). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00015 (19/126040 alleles) 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). The computational predictor REVEL gives a score of 0.323 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAMT function (BP4). To our knowledge, this variant has not been reported in the published literature. This variant is noted in ClinVar (ID 205596). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 1.1.00): PM2_Supporting, BP4. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).

Met criteria codes

• BP4: The computational predictor REVEL gives a score of 0.323 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAMT function (BP4).
• PM2_Supporting: The highest population minor allele frequency in gnomAD v2.1.1 is 0.00015 (19/126040) 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).