ClinVar Miner

Submissions for variant NM_000481.3(AMT):c.958C>T (p.Arg320Cys) (rs866625610)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000672268 SCV000797359 uncertain significance Non-ketotic hyperglycinemia 2018-01-23 criteria provided, single submitter clinical testing
Invitae RCV000672268 SCV000824862 pathogenic Non-ketotic hyperglycinemia 2018-06-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 320 of the AMT protein (p.Arg320Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with glycine encephalopathy, having been proven to be on the opposite chromosome (in trans) from a pathogenic variant in AMT in one of them (PMID: 27362913, 29300369, Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different missense substitution at this codon (p.Arg320His) has been determined to be pathogenic (PMID: 10873393, 12948742, 8005589, 12948742, 23352163). This suggests that the arginine residue is critical for AMT protein function and that other missense substitutions at this position may also be pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.

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