Variant: NM_000156.6(GAMT):c.39C>A (p.Gly13=)

CA504731736

544263 (ClinVar)

Gene: GAMT

Condition: guanidinoacetate methyltransferase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: a32a55f6-0054-4cc9-9eff-706622aad123

Approved on: 2022-06-06

Published on: 2022-10-07

HGVS expressions

NM_000156.6:c.39C>A
NM_000156.6(GAMT):c.39C>A (p.Gly13=)
NC_000019.10:g.1401438G>T
CM000681.2:g.1401438G>T
NC_000019.9:g.1401437G>T
CM000681.1:g.1401437G>T
NC_000019.8:g.1352437G>T
NG_009785.1:g.5116C>A
ENST00000252288.8:c.39C>A
ENST00000447102.8:c.39C>A
ENST00000640762.1:c.39C>A
ENST00000252288.6:c.39C>A
ENST00000447102.7:c.39C>A
NM_000156.5:c.39C>A
NM_138924.2:c.39C>A
NM_138924.3:c.39C>A

Likely Benign

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence"

• Met criteria codes: BP4 BP7 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.39C>A (p.Gly13=) variant in GAMT is a synonymous variant in exon 1. It is absent in gnomAD v2.1.1 (PM2_Supporting); however, this region has low coverage and, therefore, the allele frequency data may not be accurate. It is predicted to not impact splicing by SpliceAI and VarSeak, and the nucleotide is not highly conserved (BP4, BP7). This variant does not appear to have been reported in the published literature. It is noted in ClinVar (Variation ID: 544263). Although this variant may be rare, it has been classified as likely benign by the ClinGen Creatine Deficiency Syndromes (CCDS) Variant Curation Expert Panel (VCEP) based on the recommendation of Richards et al (PMID: 25741868) because it is a synonymous variant, the altered nucleotide is not highly conserved, computational prediction suggests no impact on splicing, and there is no additional evidence to suggest that the variant is disease-causing. GAMT-specific ACMG/AMP criteria applied, as specified by the CCDS VCEP (Specifications Version 1.1.0): PM2_Supporting, BP4, BP7. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).

Met criteria codes

• BP4: This variant is not predicted to not impact splicing by SpliceAI and VarSeak (BP4).
• BP7: It is predicted to not impact splicing by SpliceAI and VarSeak, and the nucleotide is not highly conserved (GERP rejected substitutions (RS) score -8.669) (BP7).
• PM2_Supporting: This variant is absent in gnomAD v2.1.1. However, the variant is covered in fewer than 50% of individuals in gnomAD v2.1.1 exomes and, therefore, allele frequency estimates may not be reliable (PM2_Supporting).