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
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 criteria provided, single submitter 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
Integrated Genetics/Laboratory Corporation of America RCV000412474 SCV000695761 pathogenic Non-ketotic hyperglycinemia 2016-07-14 criteria provided, single submitter clinical testing Variant summary: The c.499G>T (p.Glu167*) variant in GLDC gene is a nonsense mutation. The mutation is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. The variant is present in ExAC at a frequency of 0.000025 (3/119894 chrs tested), which does not exceed the maximum frequency for a pathogenic variant in GLDC gene (0.0026%). The variant has been reported in multiple affected individuals presented classic nonketotic hyperglycinemia (NKH) evidenced by elevated CSF glycine levels, elevated CSF:plasma glycine ratio, normal urine organic acids (Swanson, 2015; Coughlin, 2016). Taken together, the variant was classified as Pathogenic.
Invitae RCV000412474 SCV000636407 pathogenic Non-ketotic hyperglycinemia 2018-12-26 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.

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