Submissions for variant NM_000156.6(GAMT):c.11_36dup (p.Gly13fs)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV001827416	SCV004042608	pathogenic	Deficiency of guanidinoacetate methyltransferase	2023-09-12	reviewed by expert panel	curation	The NM_000156.6(GAMT):c.11_36dup (p.Gly13ProfsTer38) variant in GAMT (also reported as c.36_c.37ins26) is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 1/6 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD v2.1.1. However, the read depth is <20X at this position and therefore allele frequency data cannot be accurately assessed. Three individuals with biochemical and clinical features consistent with GAMT deficiency have been described including two with reduced creatine peak and guanidinoacetate (GAc) peak on MRS as well as elevated GAc in serum (PMID 19027335, 23660394, 24415674, 29506905) and one with deficient GAMT activity in fibroblasts (PMID 24415674) (PP4_Strong). These individuals are all compound heterozygous for the variant and a second variant in GAMT, phase unknown, including c.327G>A (PMID 19027335, 23660394; pathogenic based on assessment with the ClinGen CCDS VCEP; 0.5 points), c.133T>A (p.Trp45Arg), and c.439C>T (p.His147Tyr). The in trans data for the patients with c.133T>A (p.Trp45Arg) and c.439C>T (p.His147Tyr) will be used in the assessment of those variants and is not included here in order to avoid circular logic (PM3_Supporting). There is a ClinVar entry for this variant (Variation ID: 858462). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency. GAMT-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Cerebral Creatine Deficiencies VCEP (Specifications Version 1.1.0): PVS1, PP4_Strong, PM3_Supporting. (Classification approved by the ClinGen CCDS VCEP, September 12, 2023)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001064338	SCV001229232	pathogenic	Cerebral creatine deficiency syndrome	2023-11-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly13Profs*38) in the GAMT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAMT are known to be pathogenic (PMID: 15108290). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with GAMT-related conditions (PMID: 19027335, 23660394, 24415674). This variant is also known as c.36_37ins26. ClinVar contains an entry for this variant (Variation ID: 858462). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001827416	SCV005058875	pathogenic	Deficiency of guanidinoacetate methyltransferase	2024-03-27	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001827416	SCV002087063	pathogenic	Deficiency of guanidinoacetate methyltransferase	2021-02-24	no assertion criteria provided	clinical testing

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