ClinVar Miner

Submissions for variant NM_000170.2(GLDC):c.1166C>T (p.Ala389Val) (rs121964979)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000012769 SCV000480517 pathogenic Non-ketotic hyperglycinemia 2017-04-27 criteria provided, single submitter clinical testing Across a selection of the available literature, the GLDC c.1166C>T (p.Ala389Val) variant has been identified 25 patients with glycine encephalopathy, including in a homozygous state in 11 patients and in a compound heterozygous state in 14 patients (Applegarth et al. 2004; Dinopoulos et al. 2005; Kure et al. 2006; Swanson et al. 2015; Coughlin et al. 2016). The variant has also been identified in four unaffected family members (Dinopoulos et al. 2005). The p.Ala389Val variant was absent from 300 controls and is reported at a frequency of 0.00006 in the European (non-Finnish) population of the Exome Aggregation Consortium. The Ala389 residue is conserved. Functional expression studies in COS-7 cells showed that the variant enzyme retained from 7.9% to over 10% of the wild type enzymatic activity which may explain the mild phenotype (Dinopoulos et al. 2005; Swanson et al. 2015). The Ala389 residue is highly conserved. Based on the collective evidence, the p. Ala389Val variant is classified as pathogenic for glycine encephalopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx RCV000482511 SCV000568230 likely pathogenic not provided 2017-02-21 criteria provided, single submitter clinical testing The A389V variant in the GLDC gene has been reported previously in association with nonketotic hyperglycinemia when present in the homozygous state (Applegarth et al., 2004; Dinopoulos et al., 2005). However, a milder phenotype and phenotypic variability was reported among individuals homozygous for the A389V variant, suggesting phenotype modification by unknown environmental or genetic factors (Applegarth et al., 2004; Dinopoulos et al., 2005). The A389V variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A389V variant is a conservative amino acid substitution, which occurs at a position that is conserved across species. In vitro functional expression studies in COS7 cells showed that the mutant enzyme retained 7.9% residual activity compared to wild type (Dinopoulos et al., 2005). Therefore, the A389V variant is a strong candidate for a pathogenic variant.
Invitae RCV000012769 SCV000636349 pathogenic Non-ketotic hyperglycinemia 2019-09-25 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 389 of the GLDC protein (p.Ala389Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs121964979, ExAC 0.006%). This variant has been reported as homozygous or compound heterozygous in individuals and families affected with a mild form of glycine encephalopathy (PMID: 15824356, 16450403, 26179960, 26749113) and has been reported in individuals with a suspected nonketotic hyperglycinemia (PMID: 27362913). ClinVar contains an entry for this variant (Variation ID: 11989). Experimental studies have shown that although this missense change reduces GLDC enzymatic activity, it retains some residual activity (PMID: 15824356, 26179960). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000012769 SCV000033004 pathogenic Non-ketotic hyperglycinemia 2005-04-12 no assertion criteria provided literature only

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