Submissions for variant NM_000156.6(GAMT):c.91_92insCACGG (p.Asp31fs)

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Total submissions: 5

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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	RCV001780120	SCV003852726	likely pathogenic	Deficiency of guanidinoacetate methyltransferase	2023-03-09	reviewed by expert panel	curation	The NM_000156.6:c.91_92insCACGG (Asp31AlafsTer13)) variant in GAMT 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). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0002 (1/5042 alleles) in the East Asian population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals with GAMT deficiency. There is a ClinVar entry for this variant (Variation ID: 939992). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as likely 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, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on February 8, 2023).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001209481	SCV001380918	pathogenic	Cerebral creatine deficiency syndrome	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp31Alafs*13) 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 present in population databases (no rsID available, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with GAMT-related conditions. ClinVar contains an entry for this variant (Variation ID: 939992). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001209481	SCV001999933	uncertain significance	Cerebral creatine deficiency syndrome	2021-11-02	criteria provided, single submitter	curation	The p.Asp31fs variant in GAMT has not been previously reported in individuals with cerebral creatine deficiency syndrome but has been identified in 0.02% (1/5042) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs796052531). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#: 939992) and has been interpreted as pathogenic by Invitae. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 31 and leads to a premature termination codon 13 amino acids downstream. Loss of function of the GAMT gene is an established disease mechanism in autosomal recessive cerebral creatine deficiency syndrome. In summary, the clinical significance of the p.Asp31fs variant is uncertain. ACMG/AMP Criteria applied: PVS1 (Richards 2015).
Revvity Omics, Revvity	RCV001780120	SCV002025258	likely pathogenic	Deficiency of guanidinoacetate methyltransferase	2021-10-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001780120	SCV004198587	likely pathogenic	Deficiency of guanidinoacetate methyltransferase	2023-07-04	criteria provided, single submitter	clinical testing

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