Submissions for variant NM_000156.6(GAMT):c.570+4C>T

gnomAD frequency: 0.00039  dbSNP: rs199967562

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	RCV001272269	SCV005619899	likely benign	Deficiency of guanidinoacetate methyltransferase	2024-09-11	reviewed by expert panel	curation	The NM_000156.6:c.570+4C>T variant in GAMT is an intronic variant affecting a nucleotide within the consensus splice site of intron 5. To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest population frequency in gnomAD v4.1.0. is 0.001148 (86/74912 alleles; no homozygotes) in the African / Afircan American population, which is higher than the ClinGen CCDS VCEP’s threshold for BS1 (>0.001), and therefore meets this criterion (BS1). The computational splicing predictor SpliceAI gives a score of 0.01 for donor loss and suggests that the variant has no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 582572). In summary, this variant meets the criteria to be classified as likely benign for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 2.0.0): BS1, BP4. (Classification approved by the ClinGen Creatine Deficiency Syndromes Variant Curation Expert Panel on September 11, 2024).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000706678	SCV000835745	uncertain significance	Cerebral creatine deficiency syndrome	2022-08-10	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. This variant is present in population databases (rs199967562, gnomAD 0.1%). 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: 582572). 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	RCV001613434	SCV001838282	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
New York Genome Center	RCV001272269	SCV002548791	uncertain significance	Deficiency of guanidinoacetate methyltransferase	2021-09-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002343573	SCV002650575	uncertain significance	Inborn genetic diseases	2024-11-08	criteria provided, single submitter	clinical testing	The c.570+4C>T intronic alteration consists of a C to T substitution nucleotides after coding exon 5 in the GAMT gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV001272269	SCV001454098	uncertain significance	Deficiency of guanidinoacetate methyltransferase	2020-09-16	no assertion criteria provided	clinical testing