Submissions for variant NM_000156.6(GAMT):c.299_311dup (p.Arg105fs)

dbSNP: rs80338736

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	RCV000008800	SCV002600154	pathogenic	Deficiency of guanidinoacetate methyltransferase	2022-06-06	reviewed by expert panel	curation	The NM_000156.6:c.299_311dup (p. Arg105GlyfsTer26) in GAMT is a frameshift variant predicted to cause a premature stop codon in biologically relevant 3/6 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least 4 probands with biochemical and clinical features consistent with GAMT deficiency have been reported, including patients with elevated plasma guanidinoacetate, and absent creatine peak and evidence of guanidinoacetate peak on magnetic resonance spectroscopy (PMIDs 8651275, 19027335, 19388150, 23660394, 29506905) (PP4_Strong). These patients include one homozygote (with a homozygous affected sibling) (PMID 23234264; 0.5 points; possibly same patient reported in PMID 29506905); and a proband who is compound heterozygous for the variant and c.327G>A (pathogenic based on assessment by the ClinGen CCDS VCEP), confirmed in trans (PMID 8651275, 19027335, 24268530) (PM3). Another patient is compound heterozygous for the variant and c.233T>A (p.Val78Glu)(PMID 23660394), and another patient and her affected sibling are compound heterozygous for the variant and c.403G>A (p.Asp135Asn) (PMID 19388150), The in trans data from the latter patients will be used in the analysis of p.Val78Glu and p.Asp135Asn and is not included here to avoid circular logic (PM3_Strong). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001175 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: 8302). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 1.1.0): PVS1, PM3, PP4_Strong, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000534459	SCV000659565	pathogenic	Cerebral creatine deficiency syndrome	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg105Glyfs*26) in the GAMT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAMT are known to be pathogenic (PMID: 15108290). This variant is present in population databases (rs756953118, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with guanidinoacetatemethyltransferase (GAMT) deficiency (PMID: 8651275, 19027335, 23234264, 23660394). It has also been observed to segregate with disease in related individuals. This variant is also known as 309ins13 or c.297_309dup. ClinVar contains an entry for this variant (Variation ID: 8302). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000008800	SCV000919411	pathogenic	Deficiency of guanidinoacetate methyltransferase	2018-02-12	criteria provided, single submitter	clinical testing	Variant summary: GAMT c.299_311dup13 (p.Arg105GlyfsX26) results in a frameshift generating a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.491dupG (p.Val165fsX26)). The variant was found at a frequency of 5.2e-05 (11/210322) control chromosomes in gnomAD, predominantly observed in the European (Non-Finnish) subpopulation (11/90660) with a frequency of 0.00012. This frequency is not significantly higher than expected for a pathogenic variant in GAMT causing Guanidinoactetate methyltransferase deficiency (0.00012 vs 0.0011), allowing no conclusion about variant significance. c.299_311dup13 has been reported in the literature in multiple individuals affected with Guanidinoactetate methyltransferase deficiency either in homozygosity (Cheillan 2012) or in heterozygous form with other pathogenic (or likely pathogenic) GAMT variants in trans (e.g. Dhar 2009, Stockler 2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2017, and both of them classified it as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000534459	SCV001999926	pathogenic	Cerebral creatine deficiency syndrome	2021-11-02	criteria provided, single submitter	curation	The p.Arg105fs variant in GAMT has been reported in 5 individuals with cerebral creatine deficiency syndrome (PMID: 8651275, 19027335, 23234264, 23660394, 24268530), segregated with disease in 2 affected relatives from 2 families (PMID: 23234264, 24268530), and has been identified in in 0.01% (11/93592) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs779679242). 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 5 affected individuals, at least 1 of those was a homozygote and 2 were compound heterozygotes that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Arg105fs variant is pathogenic (Variation ID: 21065; PMID: 8651275, 19027335, 23234264, 23660394, 24268530). This variant has also been reported in ClinVar (Variation ID#: 8302) and has been interpreted as pathogenic by Integrated Genetics (Laboratory Corporation of America), OMIM, Invitae, and GeneReviews. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 105 and leads to a premature termination codon 26 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the GAMT gene is a strongly established disease mechanism in autosomal recessive cerebral creatine deficiency syndrome. The phenotype of individuals homozygous or compound heterozygous for this variant is highly specific for cerebral creatine deficiency syndrome based on strict biochemical investigations consistent with disease (PMID: 23660394, 8651275, 19027335, 23660394). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cerebral creatine deficiency syndrome. ACMG/AMP Criteria applied: PVS1, PM3_strong, PM2_supporting, PP4 (Richards 2015).
Revvity Omics, Revvity	RCV000008800	SCV002024175	pathogenic	Deficiency of guanidinoacetate methyltransferase	2021-11-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001787373	SCV002031066	pathogenic	not provided	2021-11-29	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 19027335, 8651275, 23660394, 29655203, 23234264)
Ambry Genetics	RCV002433449	SCV002746400	pathogenic	Inborn genetic diseases	2018-07-23	criteria provided, single submitter	clinical testing	The c.299_311dup13 variant, located in coding exon 2 of the GAMT gene, results from a duplication of GGGACTGGGCCCC at nucleotide position 299, causing a translational frameshift with a predicted alternate stop codon (p.R105Gfs*26). This alteration has been detected as homozygous in two individuals with GAMT deficiency (Cheillan D, Orphanet J Rare Dis 2012 Dec;7:96). In addition, this alteration has been detected in conjunction with other GAMT alterations in several individuals with GAMT deficiency and creatine deficiency syndromes (Comeaux MS, Mol. Genet. Metab. 2013 Jul;109(3):260-8; Dhar SU, Mol. Genet. Metab. 2009 Jan;96(1):38-43; St&ouml;ckler S,Am. J. Hum. Genet. 1996 May;58(5):914-22). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000008800	SCV002768340	pathogenic	Deficiency of guanidinoacetate methyltransferase	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with cerebral creatine deficiency syndrome 2 (MIM#612736). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (11 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in multiple individuals with cerebral creatine deficiency (also known as GAMT deficiency, ClinVar, PMIDs: 24071436, 24276113, 29506905). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV000008800	SCV002813872	pathogenic	Deficiency of guanidinoacetate methyltransferase	2022-01-14	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000008800	SCV004198577	pathogenic	Deficiency of guanidinoacetate methyltransferase	2024-03-28	criteria provided, single submitter	clinical testing
OMIM	RCV000008800	SCV000029010	pathogenic	Deficiency of guanidinoacetate methyltransferase	1996-05-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000008800	SCV002087040	pathogenic	Deficiency of guanidinoacetate methyltransferase	2020-09-22	no assertion criteria provided	clinical testing