Variant: NM_000156.6(GAMT):c.701C>T (p.Thr234Ile)

CA402990219

544252 (ClinVar)

Gene: GAMT

Condition: guanidinoacetate methyltransferase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 397f2859-76c3-4517-84b4-138d7c736622

Approved on: 2022-06-06

Published on: 2024-05-01

HGVS expressions

NM_000156.6:c.701C>T
NM_000156.6(GAMT):c.701C>T (p.Thr234Ile)
NC_000019.10:g.1397369G>A
CM000681.2:g.1397369G>A
NC_000019.9:g.1397368G>A
CM000681.1:g.1397368G>A
NC_000019.8:g.1348368G>A
NG_008283.1:g.18486G>A
NG_009785.1:g.9185C>T
ENST00000252288.8:c.701C>T
ENST00000640762.1:c.632C>T
ENST00000252288.6:c.701C>T
NM_000156.5:c.701C>T

Uncertain Significance

• Met criteria codes: PM2_Supporting BP4

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.701C>T variant in GAMT is a missense variant predicted to cause substitution of threonine by isoleucine at amino acid 234 (p.Thr234Ile). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00011 (1/126040) in the African / African 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 0.268 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. It has been previously noted in ClinVar (ID 544252). 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 1.1.0): PM2_Supporting, BP4. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).

Met criteria codes

• PM2_Supporting: The highest population minor allele frequency in gnomAD v2.1.1 is 0.00011 (1/126040 alleles) in the African / African American population, which is lower than the ClinGen CCDS VCEP's threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting).
• BP4: The computational predictor REVEL gives a score of 0.268 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAMT function (BP4).