ClinVar Miner

Submissions for variant NM_000481.4(AMT):c.959G>A (p.Arg320His) (rs121964985)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000012759 SCV000636431 pathogenic Non-ketotic hyperglycinemia 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 320 of the AMT protein (p.Arg320His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs121964985, ExAC 0.02%). This variant has been reported in the literature in several individuals affected with glycine encephalopathy with plasma and CSF Glycine levels diagnostic for this condition, as homozygous (PMID: 10873393, 12948742) and as compound heterozygotes (PMID: 8005589, 12948742). ClinVar contains an entry for this variant (Variation ID: 11979). Experimental studies have shown that this missense change causes a significant reduction of activity in glycine cleavage and glycine synthesis in vitro (PMID: 23352163). In summary, this variant is a rare missense change that has been reported in several affected individuals and it has been shown to disrupt protein activity. For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000012759 SCV000696806 pathogenic Non-ketotic hyperglycinemia 2017-03-09 criteria provided, single submitter clinical testing Variant summary: The AMT c.959G>A (p.Arg320His) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in the large control population database ExAC at a frequency of 0.0000745 (9/120770 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic AMT variant (0.0014049). Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Several publications show the variant segregating with disease (e.g., Toone_MGM_2000) and additional studies provide functional data suggesting that the variant is disease causing (e.g., Swanson_Ann Neurol_2015). Taken together, this variant is classified as pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV001090581 SCV001246195 pathogenic not provided 2018-01-01 criteria provided, single submitter clinical testing
OMIM RCV000012759 SCV000032994 pathogenic Non-ketotic hyperglycinemia 2001-04-01 no assertion criteria provided literature only
GeneReviews RCV000012759 SCV000086790 pathologic Non-ketotic hyperglycinemia 2013-07-11 no assertion criteria provided curation Converted during submission to Pathogenic.
Counsyl RCV000012759 SCV001132332 likely pathogenic Non-ketotic hyperglycinemia 2016-11-18 no assertion criteria provided clinical testing

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