ClinVar Miner

Submissions for variant NM_000156.6(GAMT):c.327G>A (p.Lys109=) (rs80338735)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187564 SCV000241158 pathogenic not provided 2018-12-26 criteria provided, single submitter clinical testing The c.327 G>A variant has been reported in multiple unrelated patients with GAMT deficiency (Stockler et al., 1996; Mercimek-Mahmutoglu et al., 2006; Dhar et al., 2009). The c.327 G>A variant was not observed in approximately 5,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although the c.327 G>A variant results in a synonymous substitution (K109K), this variant alters the last nucleotide of exon 2, and RNA studies indicate that this variant causes abnormal gene splicing (Stockler et al., 1996; Dhar et al., 2009). We interpret c.327 G>A as a disease-causing variant associated with GAMT deficiency.
Illumina Clinical Services Laboratory,Illumina RCV000020141 SCV000410914 pathogenic Deficiency of guanidinoacetate methyltransferase 2017-04-27 criteria provided, single submitter clinical testing The GAMT c.327G>A (p.Lys109=) variant is reported as one of the most frequently observed pathogenic variants among patients with guanidinoacetate methyltransferase deficiency accounting for 24% of disease associated alleles (Mercimek-Mahmutoglu and Salomons 2015). Across a selection of the available literature, the p.Lys109= variant has been identified in a total of 15 individuals including four in a homozygous state and 11 in a compound heterozygous state (Stockler et al. 1996; Morris et al. 2007; Dhar et al. 2009; Comeaux et al. 2013; Mercimek-Mahmutoglu et al. 2014). Unaffected heterozygous carriers of the variant were observed in two families (Stockler et al. 1996). Control data are unavailable for this variant, which is reported at a frequency of 0.00031 in the European (non-Finnish) population of the Exome Aggregation Consortium. The variant affects the last nucleotide of the splice donor site of exon 2. Experimental analysis showed the variant results in two abnormal transcripts, one from the use of a cryptic splice site in intron 2 and one resulting from skipping of exon 2. Both abnormal transcripts were identified in one compound heterozygous individual and one homozygous individual, demonstrating the effect on splicing of the variant (Stockler et al. 1996). Based on the collective evidence, the p.Lys109= variant is classified as pathogenic for guanidinoacetate methyltransferase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000655367 SCV000777297 pathogenic Cerebral creatine deficiency syndrome 2020-09-03 criteria provided, single submitter clinical testing This sequence change affects codon 109 of the GAMT mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the GAMT protein. This variant also falls at the last nucleotide of exon 2 of the GAMT coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs80338735, ExAC 0.03%). This variant has been reported in several individuals affected with guanidinoacetate methyltransferase (GAMT) deficiency and is considered one of the most common mutations in GAMT (PMID: 8651275, 22019491, 2476685, 24415674). ClinVar contains an entry for this variant (Variation ID: 21065). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this silent change causes abnormal gene splicing by inserting 44 nucleotides (PMID: 8651275). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000020141 SCV000893511 pathogenic Deficiency of guanidinoacetate methyltransferase 2018-10-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000020141 SCV000919410 pathogenic Deficiency of guanidinoacetate methyltransferase 2018-02-01 criteria provided, single submitter clinical testing Variant summary: GAMT c.327G>A (p.Lys109Lys) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5 splicing donor site. These predictions are confirmed in a publication via RT-PCR analysis (though the results were not presented for evaluation; Stockler_1996). The same publication presented data showing that the activity of GAMT is significantly reduced in two patient's liver cells compared to WT, suggesting the variant affects protein function. The variant allele was found at a frequency of 0.00019 in 197356 control chromosomes. The c.327G>A variant has been reported in the literature in numerous individuals affected with Guanidinoactetate methyltransferase deficiency, both as homozygous and compound heterozygous alleles. These data indicate that the variant is very likely to be associated with disease. Additionally, in the literature it has been referred to as one of the most common mutations associated with Guanidinoactetate methyltransferase deficiency. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, both of which classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Cytogenetics and Genomics Lab,Cyprus Institute Of Neurology and Genetics RCV000020141 SCV001443811 pathogenic Deficiency of guanidinoacetate methyltransferase 2020-06-17 criteria provided, single submitter research
GeneReviews RCV000020141 SCV000040467 pathologic Deficiency of guanidinoacetate methyltransferase 2011-08-18 no assertion criteria provided curation Converted during submission to Pathogenic.
GenomeConnect-Association for Creatine Deficiencies, Association for Creatine Deficiencies RCV000020141 SCV001156344 not provided Deficiency of guanidinoacetate methyltransferase no assertion provided phenotyping only Variant interpreted as Pathogenic and reported on 12-08-2009 by GTR ID 1006. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect facilitates ClinVar submission from the Association for Creatine Deficiencies registry and does not attempt to reinterpret the variant.
Natera, Inc. RCV000020141 SCV001454104 pathogenic Deficiency of guanidinoacetate methyltransferase 2020-09-16 no assertion criteria provided clinical testing

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