ClinVar Miner

Submissions for variant NM_000170.3(GLDC):c.2614A>T (p.Lys872Ter)

gnomAD frequency: 0.00001  dbSNP: rs1430968530
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000526391 SCV000636391 pathogenic Glycine encephalopathy 2023-11-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys872*) in the GLDC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GLDC are known to be pathogenic (PMID: 16601880). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with non-ketotic hyperglycinaemia (PMID: 27362913). ClinVar contains an entry for this variant (Variation ID: 462877). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000526391 SCV000919468 likely pathogenic Glycine encephalopathy 2018-05-25 criteria provided, single submitter clinical testing Variant summary: GLDC c.2614A>T (p.Lys872X) 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. A truncation downstream of this position has been classified as pathogenic by our laboratory (c.2891dupA (p.Tyr964X)). The variant was absent in 246210 control chromosomes (in gnomAD). c.2614A>T has been reported in the literature in individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) (Coughlin 2017). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000526391 SCV004046158 pathogenic Glycine encephalopathy criteria provided, single submitter clinical testing This nonsense variant found in exon 22 of 25 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported together with a second variant in GLDC in two individuals with nonketotic hyperglycinemia (PMID: 27362913). In particular, in one individual, the c.2614A>T was in trans with a two exon deletion (PMID: 27362913). It is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.2614A>T (p.Lys872Ter) variant is classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV005044807 SCV005679299 likely pathogenic Glycine encephalopathy 1 2024-06-12 criteria provided, single submitter clinical testing
Counsyl RCV000526391 SCV000794973 pathogenic Glycine encephalopathy 2017-10-24 no assertion criteria provided clinical testing

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