ClinVar Miner

Submissions for variant NM_000170.2(GLDC):c.1786C>T (p.Arg596Ter) (rs386833531)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000049459 SCV000789304 likely pathogenic Non-ketotic hyperglycinemia 2017-01-24 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000049459 SCV000894477 pathogenic Non-ketotic hyperglycinemia 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000049459 SCV001362672 likely pathogenic Non-ketotic hyperglycinemia 2019-04-22 criteria provided, single submitter clinical testing Variant summary: GLDC c.1786C>T (p.Arg596X) 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. The variant allele was found at a frequency of 1.2e-05 in 251482 control chromosomes (gnomAD). c.1786C>T has been reported in the literature in compound heterozygote and homozygote individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) (Gao_2017, Kure_2006). 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. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant once as pathogenic and once as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000049459 SCV001387966 pathogenic Non-ketotic hyperglycinemia 2019-07-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg596*) in the GLDC gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in several individuals affected with non-ketotic hyperglycinemia (PMID: 16450403, 28302194). ClinVar contains an entry for this variant (Variation ID: 56050). Loss-of-function variants in GLDC are known to be pathogenic (PMID: 16601880). For these reasons, this variant has been classified as Pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049459 SCV000081893 probable-pathogenic Non-ketotic hyperglycinemia no assertion criteria provided not provided Converted during submission to Likely pathogenic.

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