ClinVar Miner

Submissions for variant NM_000156.6(GAMT):c.655G>A (p.Asp219Asn) (rs753228876)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001704992 SCV000241146 uncertain significance not provided 2020-11-13 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Invitae RCV000655358 SCV000777288 uncertain significance Cerebral creatine deficiency syndrome 2020-10-01 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 219 of the GAMT protein (p.Asp219Asn). The aspartic acid residue is weakly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs753228876, ExAC 0.09%). This variant has not been reported in the literature in individuals with GAMT-related disease. ClinVar contains an entry for this variant (Variation ID: 205569). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0. The asparagine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000715738 SCV000846569 uncertain significance History of neurodevelopmental disorder 2016-05-26 criteria provided, single submitter clinical testing The p.D219N variant (also known as c.655G>A), located in coding exon 6 of the GAMT gene, results from a G to A substitution at nucleotide position 655. The aspartic acid at codon 219 is replaced by asparagine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6501 samples (13002 alleles) with coverage at this position. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis.Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Natera, Inc. RCV001275200 SCV001460076 uncertain significance Deficiency of guanidinoacetate methyltransferase 2020-01-24 no assertion criteria provided clinical testing

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