Submissions for variant NM_000156.6(GAMT):c.440_441del (p.His147fs)

dbSNP: rs1487842051

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV004596401	SCV005089678	uncertain significance	Deficiency of guanidinoacetate methyltransferase	2023-01-30	reviewed by expert panel	curation	The NM_000156.6:c.440_441del (p.His147fs) variant in GAMT is a frameshift variant predicted to cause a premature stop codon in the last 50 nucleotides of the penultimate exon of the gene and therefore to escape nonsense mediated decay. More than 10% of the protein is predicted to be removed. (PVS1_Strong). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001 (1/113542 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: 854960). In summary, this variant meets the criteria to be classified as a variant of uncertain significance 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_Strong, PM2_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001060114	SCV001224777	pathogenic	Cerebral creatine deficiency syndrome	2020-03-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the GAMT protein. Other variant(s) that disrupt this region (p.Val165Argfs*26) have been observed in individuals with GAMT-related conditions (PMID: 28438604, 11136556). This suggests that this may be a clinically significant region of the protein. This variant has not been reported in the literature in individuals with GAMT-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the GAMT gene (p.His147Profs*43). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 90 amino acids of the GAMT protein.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001060114	SCV001999917	uncertain significance	Cerebral creatine deficiency syndrome	2021-11-02	criteria provided, single submitter	curation	The p.His147fs variant in GAMT has not been previously reported in individuals with cerebral creatine deficiency syndrome but has been identified in 0.0009% (1/113542) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1487842051). 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#: 854960) 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 147 and leads to a premature termination codon 43 amino acids downstream. This termination codon occurs within the terminal 50 bases of the second to last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the GAMT gene is an established disease mechanism in cerebral creatine deficiency syndrome. In summary, the clinical significance of the p.His147fs variant is uncertain. ACMG/AMP Criteria applied: PVS1_strong, PM2_supporting (Richards 2015).