ClinVar Miner

Submissions for variant NM_000156.6(GAMT):c.59G>C (p.Trp20Ser) (rs80338734)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000008801 SCV000914270 pathogenic Deficiency of guanidinoacetate methyltransferase 2019-04-05 criteria provided, single submitter clinical testing Across a selection of literature, the GAMT c.59G>C (p.Trp20Ser) missense variant has been reported in a homozygous state in at least ten individuals with guanidinoacetate methyltransferase deficiency from six families, and in a compound heterozygous state in at least two additional affected individuals (Item et al. 2004; Caldeira Araujo et al. 2005; Mercimek-Mahmutoglu et al. 2006). In several families, parents of affected individuals homozygous for the p.Trp20Ser variant were found to be heterozygous carriers. Control data are not available for the p.Trp20Ser variant which is reported at a frequency of 0.000109 in the European (non-Finnish) population of the Genome Aggregation Database. GAMT activity was undetectable in lymphoblasts from affected individuals homozygous for the p.Trp20Ser variant (Caldeira Araujo et al. 2005). HeLa cells transfected with p.Trp20Ser variant GAMT showed no increase in GAMT activity in contrast to cells transfected with wild type GAMT where an increase in GAMT activity was demonstrated (Almeida et al. 2007). The p.Trp20Ser variant has been reported at a higher frequency in patients from Portugal. Screening for this variant on newborn blood spot cards in Portugal identified this variant in a heterozygous state in eight newborns (Almeida et al. 2007). A founder effect was suggested based on the results from this study. Based on the collective evidence, the p.Trp20Ser 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 RCV000799554 SCV000939222 pathogenic Cerebral creatine deficiency syndrome 2020-10-19 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with serine at codon 20 of the GAMT protein (p.Trp20Ser). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and serine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed to segregate with cerebral creatine deficiency syndrome in a family (PMID: 15651030) and has been observed to be homozygous or in combination with another GAMT variant in unrelated individuals affected with cerebral creatine deficiency syndrome (PMID: 15108290, 21140503, 17336114, 16855203). ClinVar contains an entry for this variant (Variation ID: 8303). Experimental studies have shown that this missense change abolishes GAMT activity (PMID: 17336114). For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000986201 SCV001135124 pathogenic not provided 2019-05-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000008801 SCV001360425 pathogenic Deficiency of guanidinoacetate methyltransferase 2019-12-09 criteria provided, single submitter clinical testing Variant summary: GAMT c.59G>C (p.Trp20Ser) results in a non-conservative amino acid change located in the Arginine N-methyltransferase 2-like domain (IPR026480) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.4e-05 in 74462 control chromosomes. c.59G>C has been reported in the literature in multiple individuals (both homozygous and compound heterozygous) affected with Guanidinoactetate methyltransferase deficiency (e.g. Mercimek-Mahmutoglu_2006, Araujo_2005). In many families it was reported to segregate with the disease (e.g. Mercimek-Mahmutoglu_2006, Araujo_2005). These data indicate that the variant is very likely to be associated with disease. GAMT activity was almost undetectable in patients homozygous for this mutation (Mercimek-Mahmutoglu_2006, Araujo_2005). Two ClinVar submitters (evaluation after 2014) cite the variant as Pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000008801 SCV000029011 pathogenic Deficiency of guanidinoacetate methyltransferase 2007-05-01 no assertion criteria provided literature only
GeneReviews RCV000008801 SCV000040470 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 RCV000008801 SCV001169665 not provided Deficiency of guanidinoacetate methyltransferase no assertion provided phenotyping only Variant interpreted as Pathogenic and reported on 07-30-2018 by GTR ID 26957. 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. RCV000008801 SCV001454106 pathogenic Deficiency of guanidinoacetate methyltransferase 2020-09-16 no assertion criteria provided clinical testing

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