Submissions for variant NM_000156.6(GAMT):c.481A>T (p.Lys161Ter)

gnomAD frequency: 0.00003  dbSNP: rs1057524499

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV003159118	SCV003852705	likely pathogenic	Deficiency of guanidinoacetate methyltransferase	2023-03-09	reviewed by expert panel	curation	The NM_000156.6:c.481A>T (p.Lys161Ter) variant in GAMT is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 5/6. While the variant is in the penultimate exon of GAMT, it is upstream of the region predicted to be missed by nonsense-mediated decay, and this is expcetd to lead 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 0.00002 (2/128668 alleles) in the European (non-Finnish) population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 392462). To our knowledge, this variant has not been reported in an individual with GAMT deficiency in the published literature. 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 March 9, 2023)
GeneDx	RCV000420204	SCV000535736	likely pathogenic	not provided	2022-02-23	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense-mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV001389010	SCV001590214	pathogenic	Cerebral creatine deficiency syndrome	2023-11-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys161*) 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 0.007%). 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: 392462). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001389010	SCV001999916	likely pathogenic	Cerebral creatine deficiency syndrome	2022-09-13	criteria provided, single submitter	curation	The p.Lys161Ter variant in GAMT has not been previously reported in individuals with cerebral creatine deficiency syndrome but has been identified in 0.002% (2/128668) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1057524499). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 392462) and has been interpreted as likely pathogenic by GeneDx and pathogenic by Invitae. This nonsense variant leads to a premature termination codon at position 161, which is predicted to lead to a truncated or absent protein. Loss of function of the GAMT gene is an established disease mechanism in cerebral creatine deficiency syndrome. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive cerebral creatine deficiency syndrome. ACMG/AMP Criteria applied: PM2_supporting, PVS1 (Richards 2015).
Baylor Genetics	RCV003159118	SCV004198581	likely pathogenic	Deficiency of guanidinoacetate methyltransferase	2023-08-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV003159118	SCV005655111	likely pathogenic	Deficiency of guanidinoacetate methyltransferase	2024-06-06	criteria provided, single submitter	clinical testing