Submissions for variant NM_000156.6(GAMT):c.328-1G>A

gnomAD frequency: 0.00001  dbSNP: rs756772965

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV001832448	SCV003852723	likely pathogenic	Deficiency of guanidinoacetate methyltransferase	2023-02-03	reviewed by expert panel	curation	The NM_000156.6:c.328-1G>A variant in GAMT occurs within the canonical splice acceptor site of intron 2. It is predicted to cause skipping of biologically-relevant-exon 3/6, resulting in a frameshift 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 0.00006 (1/15792 alleles) in the African 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: 844968). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001047942	SCV001211928	pathogenic	Cerebral creatine deficiency syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 2 of the GAMT gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GAMT are known to be pathogenic (PMID: 15108290). This variant is present in population databases (rs756772965, gnomAD 0.007%). Disruption of this splice site has been observed in individual(s) with guanidinoacetate methyltransferase (GAMT) deficiency (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 844968). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001047942	SCV001999923	uncertain significance	Cerebral creatine deficiency syndrome	2021-11-02	criteria provided, single submitter	curation	The c.328-1G>A variant in GAMT has not been previously reported in individuals with cerebral creatine deficiency syndrome but has been identified in 0.006% (1/15792) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs756772965). 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#: 844968) and has been interpreted as likely pathogenic by Invitae. This variant is located in the 5' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Loss of function of the GAMT gene is a strongly established disease mechanism in cerebral creatine deficiency syndrome. In summary, the clinical significance of the c.328-1G>A variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting, PVS1 (Richards 2015).
Baylor Genetics	RCV001832448	SCV004198569	likely pathogenic	Deficiency of guanidinoacetate methyltransferase	2024-03-05	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001832448	SCV002087037	likely pathogenic	Deficiency of guanidinoacetate methyltransferase	2017-06-16	no assertion criteria provided	clinical testing