ClinVar Miner

Submissions for variant NM_000170.2(GLDC):c.1054del (p.Thr352fs) (rs386833518)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000049446 SCV000486648 likely pathogenic Non-ketotic hyperglycinemia 2016-11-03 criteria provided, single submitter clinical testing
Invitae RCV000049446 SCV000830289 pathogenic Non-ketotic hyperglycinemia 2018-03-23 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Thr352Glnfs*65) in the GLDC gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs386833518, ExAC 0.002%). This variant has been identified as homozygous in an individual affected with non-ketotic hyperglycinaemia (PMID: 17361008). It has also been reported as heterozygous in an individual with non-ketotic hyperglycinaemia, with co-occurring allele unknown (PMID: 12126939). ClinVar contains an entry for this variant (Variation ID: 56037). Loss-of-function variants in GLDC are known to be pathogenic (PMID: 16601880). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001008774 SCV001168563 pathogenic not provided 2019-01-31 criteria provided, single submitter clinical testing The c.1054delA variant in the GLDC gene has been reported previously in two individuals with nonketotic hyperglycinemia; however, a second pathogenic variant in GLDC was not identified (Toone et al., 2002; Riche et al., 2018). The c.1054delA variant causes a frameshift starting with codon Threonine 352, changes this amino acid to a Glutamine residue, and creates a premature Stop codon at position 65 of the new reading frame, denoted p.Thr352GlnfsX65. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1054delA variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.1054delA as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000049446 SCV001362673 pathogenic Non-ketotic hyperglycinemia 2019-07-06 criteria provided, single submitter clinical testing Variant summary: GLDC c.1054delA (p.Thr352GlnfsX65) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.2e-05 in 251262 control chromosomes. c.1054delA has been reported in the literature in multiple individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) (Toone_2002, Kanno_2007, Coughlin_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049446 SCV000081880 probable-pathogenic Non-ketotic hyperglycinemia no assertion criteria provided not provided Converted during submission to Likely pathogenic.

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