Submissions for variant NM_000156.6(GAMT):c.507_521dup (p.Cys169_Ser173dup)

dbSNP: rs779931959

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	RCV002305494	SCV002600144	likely pathogenic	Deficiency of guanidinoacetate methyltransferase	2022-06-06	reviewed by expert panel	curation	The NM_000156.6:c.507_521dup (p.Cys169_Ser173dup) variant in GAMT is a protein length-changing variant (in-frame insertion) in a non-repeat region (PM4). This variant has been previously reported in at least two cases with clinical symptoms consistent with GAMT deficiency. One proband had elevated plasma GAA and was compound heterozygous for the variant and a pathogenic variant in GAMT, c.327G>A (p.Lys109=), with the variants confirmed in trans by parental testing (PMID: 23583224, 29506905; personal communication). Another proband had elevated plasma GAA and reduced cerebral creatine by MRS, pretreatment, and was compound heterozygous for the variant and c.403G>T (p.Asp135Tyr) (PMID: 19027335, 23660394) (PP4_Strong, PM3). The allelic data for the latter patient will be used in the classification of p.Asp135Tyr and was not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00000883 (1/113306 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). The computational predictors PROVEAN and MutPred-Indel gave scores consistent with a damaging effect on GAMT function, but MutationTaster suggested no impact (PP3 was not applied). There is a ClinVar entry for this variant (Variation ID: 431959). 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): PP4_strong, PM3, PM2_supporting. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).
GeneDx	RCV000497566	SCV000589566	likely pathogenic	not provided	2023-08-11	criteria provided, single submitter	clinical testing	In-frame insertion of 5 amino acids in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19027335, 29506905, 23660394, 23583224)
Invitae	RCV000695868	SCV000824392	likely pathogenic	Cerebral creatine deficiency syndrome	2023-12-26	criteria provided, single submitter	clinical testing	This variant, c.507_521dup, results in the insertion of 5 amino acid(s) of the GAMT protein (p.Cys169_Ser173dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs779931959, gnomAD 0.002%). This variant has been observed in individual(s) with creatine deficiency syndromes (PMID: 19027335, 23583224, 23660394). 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: 431959). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV002318603	SCV000849738	uncertain significance	Inborn genetic diseases	2017-05-31	criteria provided, single submitter	clinical testing	The c.507_521dup15 variant (also known as p.C169_S173dup), located in coding exon 5 of the GAMT gene, results from an in-frame duplication of 15 nucleotides at nucleotide positions 507 to 521. This results in the duplication of 5 extra residues (CNLTS) between codons 169 and 173. These amino acid positions are highly conserved in available vertebrate species. This variant has been described in a patient with GAMT deficiency who was also heterozygous for a recurrent splice site alteration; however, the phase of the alterations was not specified (Dhar SU, et al. Mol. Genet. Metab. 2009 Jan;96(1):38-43). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000695868	SCV001999906	pathogenic	Cerebral creatine deficiency syndrome	2021-11-02	criteria provided, single submitter	curation	The p.Cys169_Ser173dup variant in GAMT has been reported in at least 3 individuals with cerebral creatine deficiency syndrome (PMID: 19027335, 23583224, 29506905) and has been identified in 0.0009% (1/113306) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs370421531). 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. Of the 3 affected individuals, 1 was a compound heterozygote that carried a pathogenic variant in trans, and 2 were compound heterozygotes that carried a reported pathogenic variant with unknown phase, which increases the likelihood that the p.Cys169_Ser173dup variant is pathogenic (Variation ID: 21065, 573140 PMID: 19027335, 23583224, 29506905). This variant has also been reported in ClinVar (Variation ID#: 431959) and has been interpreted as a VUS by Invitae and Ambry Genetics and likely pathogenic by GeneDx. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant is an insertion of 5 amino acids at position 169 and is not predicted to alter the protein reading-frame. The phenotype of individuals compound heterozygous for this variant is highly specific for cerebral creatine deficiency syndrome based on strict biochemical investigations consistent with disease (PMID: 23583224, 29506905, 19027335). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cerebral creatine deficiency syndrome. ACMG/AMP Criteria applied: PM3, PM2_supporting, PM4, PP4_strong, PP3 (Richards 2015).
Baylor Genetics	RCV002305494	SCV004198586	likely pathogenic	Deficiency of guanidinoacetate methyltransferase	2023-07-11	criteria provided, single submitter	clinical testing