Submissions for variant NM_000156.6(GAMT):c.58dup (p.Trp20fs)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV003307396	SCV004009601	pathogenic	Deficiency of guanidinoacetate methyltransferase	2023-05-25	reviewed by expert panel	curation	The NM_000156.6:c.58dup (p.Trp20LeufsTer65) variant in GAMT is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 2/6 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been detected in one individual with GAMT deficiency, who was compound heterozygous for the variant and a pathogenic variant, with the phase confirmed in trans by family testing (PMID: 24766785). This individual had elevated urine GAA, deficient GAMT activity in fibroblasts and reduced creatine peak on brain MRS (PMID: 24766785) (PP4_Strong). This variant is not present in gnomAD v2.1.1 but the coverage is <20X and therefore PM2_Supporting is not met. There is no ClinVar entry for this variant. In summary, this variant meets the criteria to be classified as 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 1.1.0): PVS1, PM3, PP4_Strong. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 25, 2023)
Baylor Genetics	RCV003307396	SCV004198573	pathogenic	Deficiency of guanidinoacetate methyltransferase	2024-02-15	criteria provided, single submitter	clinical testing