ClinVar Miner

Submissions for variant NM_000170.2(GLDC):c.499G>T (p.Glu167Ter) (rs191905539)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000412474 SCV000636407 pathogenic Non-ketotic hyperglycinemia 2019-12-16 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu167*) in the GLDC gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs191905539, ExAC 0.02%). This variant has been reported as homozygous or in combination with other GLDC variants in individuals affected with glycine encephalopathy, also known as non-ketotic hyperglycinemia (PMID: 26179960). ClinVar contains an entry for this variant (Variation ID: 370365). Loss-of-function variants in GLDC are known to be pathogenic (PMID: 16601880). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000412474 SCV000695761 pathogenic Non-ketotic hyperglycinemia 2020-07-02 criteria provided, single submitter clinical testing Variant summary: GLDC c.499G>T (p.Glu167X) 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 2e-05 in 251296 control chromosomes. c.499G>T has been reported in the literature in multiple individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) in the homozygous and compound heterozygous states (Swanson_2015, Coughlin_2016). Four 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.
Ambry Genetics RCV000624546 SCV000741325 pathogenic Inborn genetic diseases 2016-01-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Counsyl RCV000412474 SCV000485665 likely pathogenic Non-ketotic hyperglycinemia 2016-10-31 no assertion criteria provided clinical testing
Division of Human Genetics,Children's Hospital of Philadelphia RCV000412474 SCV000536876 pathogenic Non-ketotic hyperglycinemia 2016-06-29 no assertion criteria provided research

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