ClinVar Miner

Submissions for variant NM_000170.2(GLDC):c.2182G>A (p.Gly728Arg)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000704610 SCV000833564 likely pathogenic Non-ketotic hyperglycinemia 2018-04-02 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 728 of the GLDC protein (p.Gly728Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in combination with another GLDC variant in individuals with suspected glycine encephalopathy (PMID: 27362913) and in an individual with an elevated CSF:plasma glycine ratio, findings that are highly specific for this condition (Invitae communication). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). A different missense substitution at this codon (p.Gly728Glu) has been determined to be pathogenic (PMID:  27362913, 26179960). This suggests that the glycine residue is critical for GLDC protein function and that other missense substitutions at this position may also be pathogenic. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has been observed in ).

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