Submissions for variant NM_000156.6(GAMT):c.570+5G>A

dbSNP: rs199678332

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000794003	SCV000933385	uncertain significance	Cerebral creatine deficiency syndrome	2022-09-01	criteria provided, single submitter	clinical testing	This sequence change falls in intron 5 of the GAMT gene. It does not directly change the encoded amino acid sequence of the GAMT protein. It affects a nucleotide within the consensus splice site. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 640879). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV001585712	SCV001819442	uncertain significance	not provided	2020-09-22	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.
Ambry Genetics	RCV002343655	SCV002650576	uncertain significance	Inborn genetic diseases	2019-06-28	criteria provided, single submitter	clinical testing	The c.570+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 5 in the GAMT gene. This nucleotide position is not well conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by BDGP to abolish the native splice donor site, but is predicted to weaken (but not abolish) the efficiency of the native splice donor site by ESEfinder; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV001830699	SCV002087014	uncertain significance	Deficiency of guanidinoacetate methyltransferase	2020-02-21	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003918271	SCV004735621	uncertain significance	GAMT-related disorder	2023-10-18	no assertion criteria provided	clinical testing	The GAMT c.575G>A variant is predicted to result in the amino acid substitution p.Arg192His. Of note, this variant is intronic (c.570+5G>A) in the primary transcript (NM_000156.6) listed in the Human Gene Mutation Database (HGMD; https://www.hgmd.cf.ac.uk/). Splicing prediction programs indicate that this variant may weaken the canonical splice donor site at the junction of exon 5 and intron 5 (Alamut Visual v1.6.1). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0057% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-1398910-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.